Novel compounds, pharmaceutical compositions, and methods for treating inflammation and pain

ABSTRACT

The present invention relates to beta-aminoethyl-substituted phenyl compounds, especially beta-aminoethoxy-substituted phenyl compounds. The present invention also relates to pharmaceutical compositions comprising a safe and effective amount of a compound of the present invention and a pharmaceutically-acceptable carrier. The present invention further relates to methods for producing analgesia and reducing inflammation, in humans and lower animals, by administering the compounds or compositions of the present invention. In addition, the present invention relates to methods for making compounds of the present invention and intermediates useful in these synthesis methods.

This application is a continuation-in-part of application Ser. No.359,598 filed June 1, 1989, now abandoned which is acontinuation-in-part of application Ser. No. 149,618 filed Feb. 12,1988, now abandoned which is a continuation-in-part of application Ser.No. 023,598 filed Mar. 9, 1987, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to certain novelbeta-aminoethyl-substituted phenyl compounds, especiallybeta-aminoethoxy-substituted phenyl compounds, which are effective asanti-inflammatory and/or analgesic agents. This invention also relatesto methods for synthesizing compounds of the present invention, andintermediates useful in these synthesis methods The present inventionfurther relates to pharmaceutical compositions containing thesecompounds, which compositions are useful for treating diseases involvinginflammation and/or pain. Finally, the present invention relates tomethods for treating diseases characterized by inflammation or pain.

Inflammation, or the "inflammatory response", is the result of complexinterconnected physiological events, including increased vascularpermeability, fluid accumulations, and the migration of a changingpopulation of inflammatory cells into the inflamed area. The clinicalmanifestations of inflammation include swelling (edema), increased localtemperature, erythema, and pain. The inflammatory response can betriggered by any of a number of causative factors, including certainbacteria, radiation, hypersensitivity to chemical agents, arthritis-likeconditions, and the like. The inflammatory response is generallybelieved to be a primary defense mechanism in the body, but, unchecked,can become excessive and can result in functional impairment.

The use of non-steroidal anti-inflammatory, anti-pyretic and analgesicdrugs, especially the salicylates, which include aspirin and aspirinderivatives, to combat inflammation and attendant pain is acceptedmedical practice. The non-steroidals are commonly employed to relievepain and inflammation associated with, for example, bursitis, arthritis,and the like.

While pain is incapable of precise definition due to its basicallysubjective nature, it can generally be said that the term refers tofeelings of distress or suffering caused by stimulation of specializednerve endings A great variety of drugs have been developed to reducepain in man and other animals; some directed to eliminating pain at itssource, and others directed to blocking the assimilation of pain by thebrain. Among the latter group of drugs that are designed to block thesensation of pain, are the analgesics, which generally relieve painwithout causing unconsciousness. Analgesics can be further classified intwo main categories: opioid analgesics, including morphine, codeine,levorphanol, and the morphine-like analgesics meperidine, and methadone;and antipyretic analgesics, such as aspirin, ibuprofen, phenacetin,acetaminophen, phenylbutazone, and indomethacin.

Although the precise pharmacological action of these analgesics isuncertain, there are certain effects which readily distinguish theopioid analgesics from the antipyretics. In particular, the antipyreticsare weak analgesics, with much of their effect in the peripheral nervoussystem, so that behavioral changes do not usually occur. Generally,these analgesics relieve only somatic pain originating from muscles,joints, tendons and fasciae, and are ineffective against deep visceralpain. However, the opioid analgesics are quite effective against alltypes of pain, with broad-based action in the central nervous system.Aside from potent analgesia, the opioids, also known as narcotics, oftenproduce effects on mood and other behavioral changes. Perhaps the mostnotable side effect of the opioid analgesics is the fact that theirrepeated use is associated with tolerance, as well as psychic andphysical dependence.

It has been recently discovered that capsaicin, a natural product ofcertain species of the genus Capsicium, induces analgesia. Capsaicin(trans-8-methyl-N-vanillyl-6-nonenamide) and "synthetic" capsaicin(N-vanillylnonanamide) are disclosed as analgesics in U.S. Pat. No.4,313,958, LaHann, issued Feb. 2, 1982. Analgesic activity of capsaicinhas also been discussed in the chemical and medical literature,including Yaksh, et al, Science, 206, pp 481-483 (1979); Jancso, et al,Naunvn-Schmiedeberg's Arch. Pharmacol., Vol. 311, pp 285-288 (1980) andHolzer et al, Eur. J. Pharm. Vol. 58, pp 511-514 (1979). U.S. Pat. No.4,238,508, Nelson, issued Dec. 9, 1980, discloses 3-hydroxyacetanilidefor use in producing analgesia in animals. European Patent Application0089710, LaHann, et al, published Sep. 28, 1983, describeshydroxyphenylacetamides with analgesic and anti-irritant activity.Similarly, analgesic and anti-irritant activity is disclosed forN-vanillyl sulfonamides in U.S. Pat. No. 4,401,663, Buckwalter, et al,issued Aug. 30, 1983; hydroxyphenyl-acetamides in U.S. Pat. No.4,424,205, LaHann, et al, issued Jan. 31, 1984; N-(3- or 4- hydroxy or3,4-dihydroxybenzyl) carbamates in U.S. Pat. No. 4,443,473, Buckwalter,et al, issued Apr. 17, 1984; N-[(substituted phenyl)methyl]-cis-monounsaturated alkenamides in U.S. Pat. No. 4,493,848,LaHann, et al, issued Jan. 15, 1985; N-(3-methoxy-4-hydroxybenzyl andphenyl) ureas and thioureas in U.S. Pat. No. 4,460,602, Buckwalter, etal, issued July 17, 1984; N-vanillylureas in European Patent Application0068590, Buckwalter, et al, published Jan. 5, 1983; N-[(substitutedphenyl)methyl] alkynamides in U.S. Pat. No. 4,532,139, Janusz, et al,issued July 30, 1985; methylene substituted N-[(substitutedphenyl)methyl] alkanamides in U.S. Pat. No. 4,544,668, Janusz, et al,issued Oct. 1, 1985; N-[(substituted phenyl)methyl]-diunsaturated amidesin U.S. Pat. No. 4,544,669, LaHann, et al, issued Oct. 1, 1985;monoalkenamides in U.S. Pat. No. 4,564,633, LaHann, et al, issued Jan.14, 1986; substituted phenylacetic acid esters in British PatentSpecification 2,168,974, Loomans, et al, published July 2, 1986;N-(substituted alkyl)alkanamides and thioamides in British PatentSpecification 2,168,976, Loomans, et al, published July 2, 1986;substituted aromatic-araalkanamides in British Patent Specification2,168,975, Janusz et al, published July 2, 1986; combinations ofcapsaicinoids and arylalkanoic acids in European Patent ApplicationPublication No. 149,545, Brand, published July 24, 1985; combinations ofcapsaicinoids and opioids in U.S. Pat. No. 4,599,342, LaHann, issuedJuly 8, 1986; European Patent Application Publication No 187,009,Janusz, et al., published July 9, 1986; European Patent ApplicationPublication No. 206,609, Berman, et al., published Dec. 30, 1986; andbeta-aminoethyl-substituted phenyl compounds in European PatentApplication No. 282,127, Gardner, et al., published Sep. 14, 1988. Thedisclosures of all these patent specifications and articles areincorporated herein by reference in their entirety.

Notwithstanding the great effort already put forth to identifyanti-inflammatory and analgesic agents, there remains a continuing needto identify new compounds and compositions which are effective fortreating inflammation and/or pain. The compounds of the presentinvention are particularly useful for such purposes since systemic dosesof these compounds can be administered to produce general analgesia andanti-inflammatory effects; or local doses can be administered to producea local analgesic effect similar to that obtained with known localanesthetics. The opiate analgesics and antipyretic analgesics which arepresently widely used for general analgesia are typically not effectivevia local administration and thus are not generally used as localanesthetics. In addition, the compounds of the present invention aresuperior to known local anesthetics since they produce analgesia withoutthe loss of mechanical sensation (i.e., "numbing") or motor coordinationwhich are typically observed with the use of known local anesthetics.The properties of the compounds of the present invention therefore makethese compounds uniquely suited for local administration before, duringand/or after local surgical operations, such as oral surgeries and minororthopedic surgeries.

An object of the present invention is therefore to provide compoundswhich can be administered to produce general analgesia and/oranti-inflammatory effects, or can be administered to produce localanesthesia without the associated negatives (e.g., numbness; loss ofmotor coordination) typically observed with known local anesthetics.Another object of the present invention is to provide compounds whichare effective anti-inflammatory and/or analgesic agents, as well aspharmaceutical compositions containing these compounds. It is thefurther object of the present invention to provide methods for treatingdiseases characterized by inflammation or pain.

A still further object of the present invention is to provide compounds,and compositions containing these compounds, which have high efficacy,high potency, and/or good therapeutic indices. An additional object isto provide compounds and compositions which cause very little or no skinirritation when administered topically.

In addition, an object of the present invention is to provide compoundswhich are easily formulated and/or dosed. Another object is to providecompounds which are substantially water soluble. The present inventionalso relates to methods for synthesizing compounds of the presentinvention which give high yields and/or which are inexpensive; and tointermediates useful in these synthesis methods.

These and other objects will become readily apparent from the detaileddescription which follows.

All percentages and ratios used herein are by weight unless otherwisespecified.

SUMMARY OF THE INVENTION

The present invention provides beta-aminoethyl-substituted phenylcompounds, and the pharmaceutically-acceptable salts and amides thereof,useful for relieving inflammation or producing analgesia in humans andlower animals, having the general structure: ##STR1## In this generalstructure, --W--X-- moiety is selected from --C(O)NH--, --C(S)NH--,--S(O)₂ NH--, --NHC(O)O--, --NHC(S)O--, --NHC(O)NH--, and --NHC(S)NH--wherein either available bond of the --W--X-- moiety is bonded to the--R moiety and the remaining bond is attached to the benzyl carbon atom(preferably --W--X-- forms an amide or thioamide moiety); --Z isselected from hydrogen, hydroxy, and methoxy (preferred is methoxy);--R¹ is selected from hydrogen, hydroxy, alkyl esters of hydroxy havingfrom about 1 to about 5 carbon atoms, alkyl having from about 1 to about5 carbon atoms, and alkoxy having from about 1 to about 5 carbon atoms,(preferred are hydrogen, hydroxy, and methyl--most preferred ishydrogen); and each --R² is independently selected from hydrogen,halogen, unsubstituted or substituted alkyl having from about to about 6carbon atoms, substituted or unsubstituted aryl, and carboxylate, or two--R² moieties are covalently bonded to form a substituted orunsubstituted alkyl, heteroalkyl, aryl or heteroaryl ring having fromabout 3 to about 8 atoms in the ring including from 0 to about 3heteroatoms. The --R group is a C₁ -C₂₄ unsubstituted or substitutedalkyl moiety which may be a straight, branched, or cyclic chain, and mayalso be saturated, monounsaturated, or polyunsaturated. Finally, the--Y-- moiety is selected from --O--, --S-- and --NR⁴ --, where R⁴ isselected from hydrogen and C₁ -C₄ alkanyl. Preferred are thebeta-aminoethoxy-substituted phenyl compounds in which the --Y-- moietyis oxygen.

This invention also provides pharmaceutical compositions comprising asafe and effective amount of the compounds of the present invention anda pharmaceutically-acceptable carrier. Also provided are methods forproducing analgesia and reducing inflammation, in humans or loweranimals, by administering the compounds or compositions of thisinvention.

The present invention further relates to methods for synthesizing thebeta-aminoethoxy-substituted phenyl compounds of the present invention.One method comprises the steps of: (1) reacting a specific phenolcompound with a specific vicinal dihalide (preferably a vicinaldibromide) to form a beta-haloethoxy phenyl compound; followed by (2)reacting the beta-haloethoxy phenyl compound with an azide salt(preferably sodium azide) to form a beta-azidoethoxy phenyl compound;followed by (3) reducing the azido moiety (preferably with SnCl₂) toform the betaaminoethoxy phenyl compound. The present invention alsorelates to the novel beta-haloethoxy phenyl compounds and novelbetaazidoethoxy phenyl compounds which are useful intermediates in thissynthesis method. Another synthesis method comprises the steps of (1)reacting a specific phenyl compound with a phthalimide salt (preferablya potassium phthalimide salt) to form a beta-phthalimidoethoxy phenylcompound; followed by (2) removing the phthalimido moiety with hydrazineto give the beta-aminoethoxy phenyl compound. The present invention alsorelates to the novel betaphthalimidoethoxy phenyl compounds which areuseful intermediates in this synthesis method. Another synthesis methodcomprises the steps of (1) reacting a specific phenol compound(preferably as its phenolic anion) with a specific aziridine compound toform a nitrogen-substituted beta-aminoethoxy phenyl compound; followedby (2) reducing the nitrogen substituent off of the nitrogen-substitutedbeta-aminoethoxy phenyl compound (preferably with sodium metal in liquidammonia) to form the beta-aminoethoxy phenyl compound.

DETAILED DESCRIPTION OF THE INVENTION Analgesic and/or Anti-inflammatoryAgents

The compounds useful in the present invention arebetaaminoethyl-substituted phenyl compounds, and thepharmaceuticallyacceptable salts and amides thereof, which are effectiveas anti-inflammatory and/or analgesic agents, having the generalstructure: ##STR2## In this general structure, the --W--X-- moiety isselected from --C(O)NH--, --C(S)NH--, --S(O)₂ NH--, --NHC(O)O--,--NHC(S)O--, --NHC(O)NH-- and --NHC(S)NH--. It is to be noted thateither available bond of the --W--X-- moiety may be bonded to the --Rmoiety, with the other bond being attached to the benzyl carbon atom.

It is preferred that for this general structure the --W-- and --X--moieties are selected from --C(O)--, --C(S)-- and --NH--, and --W--X--is an amide (i.e., --C(O)NH--) or thioamide (i.e., --C(S)NH--) moiety.Thus, the preferred --W--X-- combination forms an amide or thioamidestructure such that the compounds of the present invention are eitherphenylacetic acid amide or thioamide derivatives having the generalstructure: ##STR3## wherein ═Q is oxygen or sulfur (preferred is ═Qbeing oxygen); or vanillylamide or vanillylthioamide derivatives havingthe general structure: ##STR4## wherein ═Q is oxygen or sulfur(preferred is ═Q being oxygen).

The term "alkyl", as used herein, means carbon-containing chains whichmay be straight, branched, or cyclic; and which may be saturated,monounsaturated (i.e., one double or triple bond in the chain), orpolyunsaturated (e.g., two double bonds in the chain; two triple bondsin the chain; one double and one triple bond in the chain). Alkyl groupsmay be substituted or, preferably, unsubstituted. Preferred substituentsare selected from the group consisting of halogen, hydroxy, amino, aryl,carboxylate, and --OR³ wherein --R³ is an unsubstituted alkyl grouphaving from about 1 to about 3 carbon atoms (especially methoxy andethoxy). It is preferred that substituted alkyl groups be mono-, di- ortri-substituted, especially monosubstituted. The term "carboxylate", asused herein, means an organic carboxylic acid moiety (i.e., --CO₂ H),and the salts (e.g., sodium, potassium, calcium, tetraethylammonium) andesters (e.g., methyl ester, ethyl ester) and amides (e.g., unsubstitutedamide, N-methyl amide, N,N-dimethyl amide) thereof which are acceptablefrom a toxicity viewpoint for administration to humans or lower animals.

The terms "aryl" and "heteroaryl", as used herein, mean aryl andheteroaryl rings which may be mono-, di-, tri-, or unsubstituted,preferably monosubstituted or unsubstituted, especially unsubstituted.Additionally, heteroaryl rings comprise at least one oxygen, sulfur ornitrogen atom in the ring structure. Preferred aryls and heteroarylsinclude unsubstituted or substituted phenyl, naphthyl, pyridyl,pyrimidyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, triazolyl,tetrazolyl, thiazolyl, triazinyl, pyrrolyl, indolyl and purinyl; morepreferred aryls and heteroaryls include phenyl, pyridyl, imidazolyl,furanyl and thiophenyl; most preferred aryl is substituted orunsubstituted phenyl. Preferred substituents include halogen, hydroxy,C₁ -C₁₆ alkoxy, amino, nitro, cyano, phenyl, benzyl, benzyloxy,trifluoromethyl, formylamino, carboxylate, and C₁ -C₆ alkyl. Preferredsubstituted aryl moieties are alkylaryls, preferably unsubstituted orsubstituted where the substituent groups are independently selected fromhalogen, hydroxy, amino, and carboxy groups; most preferred alkylarylbeing a methylphenyl group.

As used herein, saturated alkyl groups are referred to as "alkanyl";unsaturated alkyl groups comprising double bonds in the chain arereferred to as "alkenyl" (preferred are chains having the double bondsin the "Z" geometric configuration); and unsaturated alkyl groupscomprising triple bonds in the chain are referred to as "alkynyl". Thedesignation of geometric configurations for any double bonds present incompounds of the present invention utilizes the art-known nomenclature"Z" and "E", and is fully described in Morrison and Boyd, OrganicChemistry, Third Edition (Allyn and Bacon, Inc., Boston; 1973), pp.131-133 and 148-151; and March, Advanced Organic Chemistry, SecondEdition (McGraw-Hill Book Company, New York; 1977), pp. 86-124; thedisclosures of both these references being incorporated herein byreference in their entirety.

In the structures herein, the --R¹ moiety is selected from hydrogen,hydroxy, alkyl esters of hydroxy having from about 1 to about 5 carbonatoms, alkyl having from about 1 to about 5 carbon atoms, and alkoxyhaving from about 1 to about 5 carbon atoms, (especially hydrogen,hydroxy, and methyl), with preferred --R¹ being hydrogen. The --Z moietyis selected from hydrogen, hydroxy, and methoxy; with preferred --Zbeing selected from hydroxy and methoxy. Most preferred --Z is methoxy.

The --R² moieties are each independently selected from hydrogen,halogen, unsubstituted or substituted alkyl having from about 1 to about5 carbon atoms, substituted or unsubstituted aryl, and carboxylate, ortwo --R² moieties are covalently bonded to form a substituted orunsubstituted alkyl, heteroalkyl, aryl or heteroaryl ring having fromabout 3 to about 8, preferably 3-6, atoms in the ring including from 0to about 3 heteroatoms. It is preferred that no more than two --R² 'sare other than hydrogen. Preferred --R² substituents other than hydrogeninclude unsubstituted and substituted C₁ -C₆ alkyl and unsubstituted andsubstituted phenyl.

It is preferred that at least one --R² on the alpha carbon atom (i.e.,the carbon atom bonded directly to the --Y-- moiety) be a hydrogen.Preferred also is all --R² being selected from hydrogen and hydroxyalkylhaving from about 1 to about 5 carbon atoms (especially 5-hydroxypentyl,2-hydroxybutyl or hydroxymethyl). Preferred also is all --R² beingselected from hydrogen and aminoalkyl having from about 1 to about 5carbon atoms (especially 5-aminopentyl, 2-aminobutyl, aminomethyl oraminoethyl). Preferred also is all --R² being selected from hydrogen andsubstituted or unsubstituted aryl (especially phenyl or methylphenyl).Also preferred is where one --R² on each of the alpha and beta carbonatoms is hydrogen and the other --R² 's are bonded to form an aryl orheteroaryl ring, especially phenyl. Also preferred is where both --R² onthe alpha carbon atom are hydrogen and at most only one --R² is otherthan hydrogen on the beta carbon atom (the carbon atom directly attachedto the alpha carbon atom) and is selected from the group consisting ofalkyl, hydroxyalkyl, aminoalkyl and substituted or unsubstituted aryls(especially hydroxymethyl, aminomethyl, aminoethyl, phenyl andmethylphenyl). Preferred also is all --R² being selected from hydrogenand alkyl having from about 1 to about 5 carbon atoms (especiallymethyl). More preferred is at most only one --R² being other thanhydrogen, and most preferred is all --R² being hydrogen.

Particularly preferred is where both --R² on the alpha carbon atom arehydrogen and both --R² on the beta carbon atom are unsubstituted orsubstituted alkyl or are covalently bonded to form a substituted orunsubstituted alkyl or heteroalkyl ring having from about 3 to about 8atoms, including from 0 to about 3 heteroatoms, in the ring. As usedherein, "heteroatoms" means atoms other than carbon that can covalentlybond to at least two other atoms and become part of a stable ringstructure. Preferred heteroatoms are N, O and S. More preferred --R² onthe beta carbon atom are unsubstituted or substituted C₁ -C₆ alkyl, morepreferably C₁ -C₄ alkyl, more preferably still C₁ -C₂ alkyl. Alsopreferred are the two --R² moieties on the beta carbon atom beingcovalently bonded to form a substituted or unsubstituted alkyl ringhaving from about 3 to about 6 carbon atoms, more preferably 3 or 4carbon atoms in the ring. Preferred --R² alkyl moieties on the betacarbon atom are saturated or unsaturated having a single double ortriple bond, more preferred is that both --R² on the beta carbon beunsubstituted or substituted alkanyl or covalently bonded to form analkanyl ring. Preferred substituents of the --R² alkyl moieties on thebeta carbon are hydroxy, amino, thiol and carboxylate, especiallyhydroxy and amino. More preferred is both --R² alkyl moieties on thebeta carbon being unsubstituted. More preferred still is that both --R²on the beta carbon atom are methyl or ethyl, especially methyl.

The --Y-- moiety is selected from --O--, --S-- and --NR⁴ --, where R⁴ isselected from hydrogen and C₁ -C₄ alkanyl; preferably R⁴ is hydrogen.Preferred --Y-- is --O-- which forms the beta-aminoethoxy-substitutedphenyl compounds having the general structure: ##STR5##

The --R group in the structures herein is an alkyl group having fromabout 1 to about 24 carbon atoms, preferably from about 6 to about 22carbon atoms, and more preferably from about 14 to about 22 (especiallyfrom about 16 to about 20) carbon atoms for unsaturated alkyl groups andfrom about 6 to about 14 (especially from about 8 to about 12) carbonatoms for saturated alkyl groups.

Preferred --R groups are arylalkyl moieties where the alkyl portion hasfrom 1 to about 12 carbon atoms, preferably from 1 to about 6 carbonatoms, more preferably 1 or 2 carbon atoms. The aryl portion of such --Rgroup is preferably unsubstituted or substituted phenyl. Preferredsubstituents include halogen, nitro, cyano, phenyl, benzyl, benzyloxy,trifluoromethyl, formylamino, C₁ -C₁₆ alkoxy and C₁ -C₄ alkyl.

Preferred --R groups are straight and branched chain alkanyl, straightand branched chain monounsaturated alkyl, straight and branched chaindiunsaturated alkyl, and straight and branched chain triunsaturatedalkyl. More preferred --R groups are selected from straight and branchedchain alkanyl, straight and branched chain alkenyl having one doublebond, straight and branched chain alkenyl having two double bonds, andstraight and branched chain alkenyl having three double bonds. Mostpreferred --R groups are selected from straight chain alkanyl andstraight chain alkenyl having one double bond. Such preferred --R groupsare preferably unsubstituted.

The preferred --R groups are as follows. For the compounds of thepresent invention which are phenylacetic acid amide or thioamidederivatives, particularly the beta-aminoethoxy-substituted compoundshaving the general structure: ##STR6## the preferred --R groups areselected from n-hexanyl, n-heptanyl, n-octanyl, n-nonanyl, n-decanyl,n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, tetradecenyl,pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl,eicosenyl, docosenyl, octadecadienyl, nonadecadienyl, eicosadienyl,octadecatrienyl, eicosatrienyl, eicosatetraenyl, octadecynyl,nonadecynyl, eicosynyl, and docosynyl. More preferred --R groups areselected from n-octanyl, n-nonanyl, n-decanyl, 9E- or 9Z-tetradecenyl,9E- or 9Z-hexadecenyl, 9E- or 9Z-octadecenyl, 6E- or 6Z-octadecenyl,11E- or 11Z-octadecenyl, 10E- or 10Z-nonadecenyl, 13E- or 13Z-docosenyl,9-methylene-1-octadecanyl, 9Z, 12Z-octadecadienyl, 9E,12E-octadecadienyl, 9Z, 12E-octadecadienyl, 9Z, 11E-octadecadienyl, 10E,13E-nonadecadienyl, 11E, 14E-eicosadienyl, 9Z, 12Z, 15Z-octadecatrienyl,6Z, 9Z, 12Z-octadecatrienyl, 11Z, 14Z, 17Z-eicosatrienyl, 5Z, 8Z, 11Z,14Z-eicosatetraenyl, and 9-octadecynyl Most preferred --R groups aren-octanyl, n-nonanyl, and 9Z-octadecenyl.

For the compounds of the present invention which are vanillylamide orvanillylthioamide derivatives, particularly thebeta-aminoethoxy-substituted compounds having the general structure:##STR7## the preferred --R groups are selected from n-hexanyl,n-heptanyl, n-octanyl, n-nonanyl, n-decanyl, n-undecanyl, n-dodecanyl,n-tridecanyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl,heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, docosenyl,heptadecadienyl, octadecadienyl, nonadecadienyl, eicosadienyl,heptadecatrienyl, octadecatrienyl, nonadecatrienyl, eicosatrienyl,nonadecatetraenyl, heptadecynyl, octadecynyl, nonadecynyl, andeicosynyl. More preferred --R groups are selected from n-heptanyl,n-octanyl, n-nonanyl, 8E- or 8Z-tridecenyl, 8E- or 8Z-pentadecenyl, 8E-or 8Z-heptadecenyl, 5E- or 5Z-heptadecenyl, 10E- or 10Z-heptadecenyl,9E- or 9Z-octadecenyl, 12E- or 12Z-nonadecenyl,8-methylene-1-heptadecanyl, 8Z, 11Z-heptadecadienyl, 8E,11E-heptadecadienyl, 8Z, 11E-heptadecadienyl, 8Z, 10E-heptadecadienyl,9E, 12E-octadecadienyl, 10E, 13E-nonadecadienyl, 8Z, 11Z,14Z-heptadecatrienyl, 5Z, 8Z, 11Z-heptadecatrienyl, 10Z, 13Z,16Z-nonadecatrienyl, 4Z, 7Z, 10Z, 13Z-nonadecatetraenyl, and8-heptadecynyl. Most preferred --R groups are n-heptanyl, n-octanyl and8Z-heptadecenyl (i.e., oleoyl amide).

The term "pharmaceutically-acceptable salts and amides", as used herein,means the compounds in their salt or amide form which have the samegeneral pharmacological properties as the basic amino form from whichthey are derived, and which are acceptable from a toxicity viewpoint.Pharmaceutically-acceptable salts include ammonium salts derived frominorganic acids (e.g., HCl, HBr, NaHSO₄, H₂ CO₃), and ammoniumcarboxylic acid salts derived from organic carboxylic acids (e.g.,acetic acid; gluconic acid; citric acid; glucouronic acid; galactouronicacid; fumaric acid; gentisic acid; lactobionic acid; benzoic acid).Pharmaceutically-acceptable amides include those derived from organiccarboxylic acids (e.g., acetic acid amides) including amino acids (e.g.,glycine amides). Preferred are the ammonium carboxylic acid saltsderived from organic carboxylic acids, especially the acetate andgluconate salts.

Compounds of the present invention include, for example,N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide havingthe structure: ##STR8##N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-thiooctadecenamidehaving the structure: ##STR9##N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenyl-sulfonamidehaving the structure: ##STR10##N-((4-(2-aminoethoxy)-3-hydroxyphenyl)-methyl)-9Z-octadecenamide havingthe structure: ##STR11##N-((4-(2-aminoethoxy)-phenyl)-methyl)-9Z-octadecenamide having thestructure: ##STR12##N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanamide having thestructure: ##STR13##N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-thiononanamide;((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanylsulfonamide;N-((4-(2-aminoethoxy)-3-hydroxyphenyl)-methyl)-nonanamide;N-((4-(2-aminoethoxy)-phenyl)-methyl)-nonanamide;N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamidehaving the structure: ##STR14##N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(1-aminocyclopropanemethoxy)cyclopropanemethoxy)-3-methoxyphenyl)methyl)-9Z-octadecenamidehaving the structure: ##STR15##N-((4-(1-aminocyclopentanemethoxy)-3-methoxyphenyl)methyl)-9Z-octadecenamidehaving the structure: ##STR16##N-((4-(2(S)-amino-3-methylbutoxy)-3-methoxyphenyl)-methyl)9Z-octadecenamidehaving the structure: ##STR17## N-((4-(2-(carboxylicacid)-2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide havingthe structure: ##STR18##N-((4-(2-amino-3-hydroxypropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamidehaving the structure: ##STR19##N-((4-(2-aminocyclopentoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-amino-3-hydroxypropoxy)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(2-amino-3-(carboxylicacid)-propoxy)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-octadecanamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9-methylene-1-octadecanamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-11Z, 14Z,17Z-eicosatrienamide; N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-5Z,8Z, 11Z, 14Z-eicosatetraenamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9-octadecynamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-tetradecenylamide;N-((4-(2-aminoethoxy)3-methoxy-phenyl)-methyl)-9Z-hexadecenamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9E-octadecenamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-13Z-docosenamide;N-((4(2-aminoethoxy)-3-methoxyphenyl)-methyl)-hexanamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-octanamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-decanamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-tetradecanamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z,12Z-octadecadienamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z,12Z-thiooctadecadienamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)dodecanamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)hexadecanamide;N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide having thestructure: ##STR20##N-(9Z-octadecenyl)-4-(2-amino-2-methylpropoxy)-3-methoxyphenyl acetamidehaving the structure: ##STR21##N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylthioacetamide havingthe structure: ##STR22##N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxybenzylsulfonamide havingthe structure: ##STR23##N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-hydroxyphenylacetamide;N-(9Z-octadecenyl)-4-(2-aminoethoxy)-phenylacetamide;N-octanyl4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-octanyl-4-(2-aminoethoxy)-3-methoxyphenylthioacetamide;N-octanyl-4-(2-aminoethoxy)-3-methoxybenzylsulfonamide;N-octanyl-4-(2-aminoethoxy)-3-hydroxyphenylacetamide;N-octanyl-4-(2-aminoethoxy)-phenylacetamide;N-(9Z-octadecenyl)-4-(2-methyl-2-aminopropoxy)-3-methoxyphenylacetamide;N-octadecanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-(9-methylene-1-octadecanyl)-4-(2-aminoethoxy)-3methoxyphenylacetamide;N-(11Z, 14Z,17Z-eicosatrienyl)4-(2-aminoethoxy)-3-methoxyphenylacetamide; N-(5Z, 8Z,11Z, 14Z-eicosatetraenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-(9-octadecynyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-(9Z-tetradecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-(9Z-hexadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-(9E-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-(13Z-docosenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-hexanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-nonanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-decanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-tetradecanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide; N-(9Z,12Z-octadecadienyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-dodecanyl-4 -(2-aminoethoxy)-3-methoxyphenylacetamide;N-hexadecanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N((4-(2-amino-2-carboxyethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-aminoethylamino)-3-methoxyphenyl)-methyl)-9Z-octadecenamidehaving the structure: ##STR24##N-((4-(2-aminoethylamino)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(2-aminoethylamino)-3-methoxyphenyl)-methyl)octanamide;N-(9Z-octadecenyl)-4-(2-aminoethylamino)-3-methoxyphenylacetamide havingthe structure: ##STR25##N-octanyl-4-(2-aminoethylamino)-3-methoxyphenylacetamide;N-((4-(2-aminoethylamino)-3-methoxyphenyl)-methyl)-9Z-thiooctadecenamide;N-((4-(2-aminoethylamino)-3-methoxyphenyl)methyl)-thiononanamide;N-(9Z-octadecenyl)-4-(2-aminoethylamino)-3-methoxyphenylthioamide;N-((4-mercapto-S-(2-aminoethyl)-3-methoxyphenyl)-methyl)-nonanamidehaving the structure: ##STR26##N-((4-mercapto-S-(2-aminoethyl)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-mercapto-S-(2-aminoethyl)-3-methoxyphenyl)-methyl)-9Z-octanamide;N-(9Z-octadecenyl)-4-(mercapto-S-(2-aminoethyl))-3-methoxyphenylacetamide;N-octanyl-4-(mercapto-S-(2-aminoethyl))-3-methoxyphenylacetamide;N-((4-mercapto-S-(2-aminoethyl)-3-methoxyphenyl)-methyl)-9Z-thiooctadecenamide;N-((4-mercapto-S-(2-aminoethyl)-3-methoxyphenyl)-methyl)-thiononanamide;N-(9Z-octadecenyl)-4-(mercapto-S-(2-aminoethyl))-3-methoxyphenylthioacetamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)methyl)-9Z-octadecenylcarbamatehaving the structure: ##STR27##N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenylthiocarbamatehaving the structure: ##STR28##N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanylcarbamate;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanylthiocarbamate;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)octanylcarbamate;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-octanylthiocarbamate;N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxybenzylcarbamate having thestructure: ##STR29##N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxybenzylthiocarbamate;N-octanyl-4-(2-aminoethoxy)-3-methoxybenzylcarbamate;N-octanyl-4-(2-aminoethoxy)-3-methoxybenzylthiocarbamate;N-((4-(2aminoethoxy)-3-methoxyphenyl)-methyl)-N'-(9Z-octadecenyl)ureahaving the structure: ##STR30##N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-N'-(9Z-octadecenyl)thioureahaving the structure: ##STR31##N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-N'-nonanylurea;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-N'-nonanylthiourea;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-N'-octanylurea;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)N'-octanylthiourea; andthe pharmaceutically-acceptable salts and amides thereof.

Preferred compounds of the present invention areN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2(S)-amino-3-methylbutoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-octanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-((4-(2-amino-3-hydroxypropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-amino-2-carboxyethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;and the pharmaceutically-acceptable salts and amides thereof. Mostpreferred compounds of the present invention areN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;and the pharmaceutically-acceptable salts and amides thereof.

In order to determine and assess pharmacological activity, testing ofthese compounds in animals is carried out using various assays known tothose skilled in the art. Thus, analgesic activity may be tested inart-known models such as the acetylcholine and phenylquinone models inmice, the Randall-Selitto model in rats, and the hot-plate test in miceor rats. The anti-inflammatory activity of the compounds can beconveniently demonstrated using an assay designed to test the ability ofthese compounds to antagonize the local edema which is characteristic ofthe inflammatory response. Examples of such known tests include thecarrageenan rat edema test, the oxazolone-induced inflamed mouse eartest, and the arachidonic acid-induced inflamed mouse ear test. Anotheruseful art-known test is the adjuvant arthritis test.

These and other appropriate tests for pharmacological activity aredisclosed and/or referred to in U.S. Pat. No. 4,313,958, LaHann, issuedFebruary 2, 1982; Yaksh, et al., Science. 206. pp. 481-483 (1979);Jancso, et al., Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 311, pp.285-288 (1980); Holzer et al., Eur. J. Pharm., Vol., 58, pp. 511-514(1979); U.S. Pat. No. 4,238,508, Nelson, issued Dec. 9, 1980; EuropeanPatent Application 089710, LaHann, et al., published Sep. 28, 1983; U.S.Pat. No. 4,401,663, Buckwalter, et al., issued Aug. 30, 1983; U.S. Pat.No. 4,424,205, LaHann, et al., issued Jan. 31, 1984; U.S. Pat. No.4,443,473, Buckwalter, et al., issued Apr. 17, 1984; U.S. Pat. No.4,493,848, LaHann, et al., issued Jan. 15, 1985; U.S. Pat. No.4,460,602, Buckwalter, et al., issued July 17, 1984; European PatentApplication 0068590, Buckwalter, et al., published Jan. 5, 1983; U.S.Pat. No. 4,532,139, Janusz, et al., issued July 30, 1985; U.S. Pat. No.4,544,668, Janusz, et al., issued Oct. 1, 1985; U.S. Pat. No. 4,544,669,LaHann, et al., issued Oct. 1, 1985; U.S. Pat. No. 4,564,633, LaHann, etal., issued Jan. 14, 1986; British Patent Specification 2,168,974,Loomans, et al., published July 2, 1986; British Patent Specification2,168,976, Loomans, et al., published July 2, 1986; British PatentSpecification 2,168,975, Janusz, et al., published July 2, 1986;European Patent Application Publication No. 149,545, Brand, publishedJuly 24, 1985; U.S. Pat. No. 4,599,342, LaHann, issued July 8, 1986;European Patent Application Publication No. 187,009, Janusz, et al.,published July 9, 1986; and European Patent Application Publication No.206,609, Berman, et al., published Dec. 30, 1986; the disclosure of allthese patent specifications and articles being incorporated herein byreference in their entirety. Certain of these tests for pharmacologicalactivity are also described in more detail in the Examples providedhereinafter.

As noted hereinbefore, capsaicin and a wide variety of other substitutedphenyl compounds are known to have analgesic and/or anti-inflammatoryactivity. Typically, however, these compounds are very difficult toformulate and dose due to insolubility in water. Attempts to improvewater solubility for these types of compounds, for example by addingcertain hydrophilic substituents to the phenyl ring, results incompounds which are not efficacious. Surprisingly, however, thebeta-aminoethyl-substituted phenyl compounds of the present invention(which are chemically very similar to non-efficacious compounds havinghydrophilic substituents) are substantially water soluble and areefficacious as analgesic and/or anti-inflammatory agents. In addition,relative to the previously disclosed capsaicinoid and phenylacetamidecompounds which have demonstrated analgesic and/or anti-inflammatoryactivity, the compounds of the present invention are substantially morewater soluble, are more efficacious and/or more potent particularly whenadministered orally, and are generally less irritating to skin.

The compounds of the present invention are prepared fromreadily-available materials. Techniques useful for the preparation ofthe present compounds, and starting materials for the preparation of thepresent compounds, are described in U.S. Pat. No. 4,313,958, LaHann,issued Feb. 2, 1982; U.S. Pat. No. 4,238,508, Nelson, issued Dec. 9,1980; European Patent Application 0089710, LaHann, et al., publishedSep. 28, 1983; U.S. Pat. No. 4,401,663, Buckwalter, et al., issued Aug.30, 1983; U.S. Pat. No. 4,424,205, LaHann, et al., issued Jan. 31, 1984;U.S. Pat. No. 4,443,473, Buckwalter, et al., issued Apr. 17, 1984; U.S.Pat. No. 4,493,848, LaHann, et al., issued Jan. 15, 1985; U.S. Pat. No.4,460,602, Buckwalter, et al., issued July 17, 1984; European PatentApplication 0068590, Buckwalter, et al., published Jan. 5, 1983; U.S.Pat. No. 4,532,139, Janusz, et al., issued July 30, 1985; U.S. Pat. No.4,544,668, Janusz, et al., issued Oct. 1, 1985; U.S. Pat. No. 4,544,669,LaHann, et al., issued Oct. 1, 1985; U.S. Pat. No. 4,564,633, LaHann, etal., issued Jan. 14, 1986; British Patent Specification 2,168,974,Loomans, et al., published July 2, 1986; British Patent Specification2,168,976, Loomans, et al., published July 2, 1986; British PatentSpecification 2,168,975, Janusz, et al., published July 2, 1986;European Patent Application Publication No. 149,545, Brand, publishedJuly 24, 1985; U.S. Pat. No. 4,599,342, LaHann, issued July 8, 1986;European Patent Application Publication No. 187,009, Janusz, et al.,published July 9, 1986; and European Patent Application Publication No.206,609, Berman, et al., published Dec. 30, 1986; the disclosure of allthese patent specifications being incorporated herein by reference intheir entirety. Representative procedures for synthesizing compounds ofthe present invention are provided hereinafter.

The compounds of the present invention typically comprise from about0.00001% to about 99.9% by weight of the pharmaceutical compositions ofthe present invention, preferably from about 0.0001% to about 50%, andmost preferably from about 0.0001% to about 25%.

Pharmaceutically-acceptable Carrier

In addition to the pharmaceutical agent as described hereinbefore, thepharmaceutical compositions of the present invention essentiallycomprise a pharmaceutically-acceptable carrier. The term"pharmaceutically-acceptable carrier", as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to a human or lower animal. Theterm "compatible", as used herein, means that the components of thepharmaceutical compositions are capable of being commingled with thecompound of the present invention, and with each other, in a manner suchthat there is no interaction which would substantially reduce thepharmaceutical efficacy of the pharmaceutical composition under ordinaryuse situations. Pharmaceutically-acceptable carriers must, of course, beof sufficiently high purity and sufficiently low toxicity to render themsuitable for administration to the human or lower animal being treated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers are sugars such as lactose, glucoseand sucrose; starches such as corn starch and potato starch; celluloseand its derivatives, such as sodium carboxymethylcellulose,ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin;talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oilssuch a peanut oil, cottonseed oil, sesame oil, olive oil, corn oil andoil of theobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; sugar; alginic acid; pyrogen-freewater; isotonic saline; phosphate buffer solutions; cocoa butter(suppository base); emulsifiers, such as the Tweens®; as well as othernon-toxic compatible substances used in pharmaceutical formulations.Wetting agents and lubricants such as sodium lauryl sulfate, as well ascoloring agents, flavoring agents, excipients, tableting agents,stabilizers, antioxidants, and preservatives, can also be present. Othercompatible pharmaceutical additives and actives (e.g., NSAI drugs; painkillers; muscle relaxants) may be included in thepharmaceutically-acceptable carrier for use in the compositions of thepresent invention. For example, art-known local anesthetics may beincluded in the pharmaceutically-acceptable carrier (e.g., benzylalcohol; Novocaine®; lidocaine).

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the compounds of the present invention is basicallydetermined by the way the compound is to be administered. The preferredmodes of administering the compounds of the present invention are byinjection, orally and topically. If the compound is to be injected, thepreferred pharmaceutically-acceptable carrier is sterile, physiologicalsaline, the pH of which has been adjusted to about 4. Suitablepharmaceutically-acceptable carriers for topical application includethose suited for use in creams, gels, tapes and the like; and for oraladministration include those suited for tablets and capsules.

The pharmaceutically-acceptable carrier employed in conjunction with thecompounds of the present invention is used at a concentration sufficientto provide a practical size to dosage relationship. Thepharmaceutically-acceptable carriers, in total, may comprise from about0.1% to about 99.99999% by weight of the pharmaceutical compositions ofthe present invention, preferably from about 50% to about 99.9999%, andmost preferably from about 75% to about 99.9999%.

Total single dosages of the compounds of the present invention presentin pharmaceutical compositions herein are generally from about 1 ug toabout 10 g. Preferred single dosages are from about 1 ug to about 3500mg; more preferred are from about 1 ug to about 1000 mg; and mostpreferred are from about 1 ug to about 600 mg.

Specific oral, topical, and injectable formulations useful in thisinvention are described in the following U.S. Pat. Nos. , allincorporated by reference herein: U.S. Pat. No. 4,401,663, Buckwalter,et al, issued Aug. 30, 1983; U.S. Pat. No. 4,424,205, LaHann, et al,issued Jan. 31, 1984; U.S. Pat. No. 4,443,473, Buckwalter, et al, issuedApr. 12, 1984; U.S. Pat. No. 4,493,848, LaHann, et al, issued Jan. 15,1984. Representative pharmaceutical compositions of the presentinvention are provided in the Examples hereinafter.

Pharmaceutically-acceptable carriers suitable for the preparation ofunit dosage forms for oral administration and injection, and dosageforms for topical application are well-known in the art. Their selectionwill depend on secondary considerations like taste, cost, and/or shelfstability, which are not critical for the purposes of the presentinvention, and can be made without difficulty by a person skilled in theart. Pharmaceuticallyacceptable carriers useful in the compositions ofthe present invention are described more fully hereinafter.

A. Oral Dose Forms:

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules, bulk powders and microcapsules of the drug.These oral forms comprise a safe and effective amount, usually at leastabout 5%, and preferably from about 25% to about 50% of the compound ofthe present invention. Tablets can be compressed, enteric-coated,sugar-coated or filmcoated containing suitable binders, lubricants,surfactants, diluents, disintegrating agents, coloring agents, flavoringagents, preservatives, flow-inducing agents, and melting agents. Liquidoral dosage forms include aqueous and nonaqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules, containing suitable solvents, preservatives,emulsifying agents, suspending agents, diluents, sweeteners, meltingagents, coloring agents, and flavoring agents. Preferred carriers fororal administration include gelatin and propylene glycol. Specificexamples of pharmaceutically-acceptable carriers and excipients that maybe used in formulating oral dosage forms containing compounds of thepresent invention are described in U.S. Pat. No. 3,903,297, Robert,issued Sep. 2, 1975, incorporated by reference herein. Techniques andcompositions for making solid oral dosage forms are described inMarshall, "Solid Oral Dosage Forms," Modern Pharmaceutics. Vol. 7,(Banker and Rhodes, editors), 359-427 (1979), incorporated herein byreference. Techniques and compositions for making tablets (compressed,formulas and molded), capsules (hard and soft gelatin) and pills aredescribed in Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (1980), incorporated herein by reference.

The preferred unit dosage form for oral administration is tablets,capsules and the like, comprising a safe and effective amount of acompound of the present invention. Preferably oral dose forms comprisefrom about 10 mg to about 3500 mg of a compound of the presentinvention, more preferably from about 25 mg to about 1000 mg, and mostpreferably from about 50 mg to about 600 mg.

B. Topical Dose Forms:

The compositions of the present invention can also be administeredtopically to a biological subject, i.e., by the direct laying on orspreading of the composition on epidermal or epithelial tissue. Suchcompositions include lotions, creams, solutions, gels and solids. Thesetopical compositions comprise a safe and effective amount, usually fromabout 0.1% to about 10%, and preferably from about 1% to about 5%, ofthe compound of the present invention. Suitable carriers for topicaladministration of these compounds preferably remain in place on the skinas a continuous film and resist being washed off easily by perspirationor by immersion in water. Generally, the carrier is either organic innature or an aqueous emulsion and capable of having the analgesic and/oranti-inflammatory agent dispersed or dissolved therein. The carrier mayinclude pharmaceutically-acceptable emollients, skin penetrationenhancers, coloring agents, fragrances, emulsifiers, thickening agents,and solvents. A more detailed description of such forms follows:

1. Lotions

The lotions can comprise an effective amount (preferably from about 0.1%to about 10%) of the compound of the present invention; from 1% to 25%,preferably from 3% to 15%, of an emollient; the balance being water, aC₂ or C₃ alcohol, or a mixture of water and the alcohol. Severalemollients are known. Examples of such emollients are as follows:

a. Hydrocarbon oils and waxes. Examples are mineral oil, petrolatum,paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, andperhydrosqualene.

b. Silicone oils, such as dimethylpolysiloxanes,methylphenylpolysiloxanes, water-soluble and alcohol-solublesilconeglycol copolymers.

c. Triglyceride fats and oils such as those derived from vegetable,animal and marine sources. Examples include castor oil, safflower oil,cotton seed oil, corn oil, olive oil, cod liver oil, almond oil, avocadooil, palm oil, sesame oil, and soybean oil.

d. Acetoglyceride esters, such as acetylated monoglycerides.

e. Ethoxylated glycerides, such as ethoxylated glyceryl monostearate.

f. Alkyl esters of fatty acids having 10 to 20 carbon atoms. Methyl,isopropyl and butyl esters of fatty acids are useful herein. Examplesinclude hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropylpalmitate, isopropyl myristate, decyl oleate, isodecyl oleate, hexadecylstearate, decyl stearate, isopropyl isostearate, diisopropyl adipate,diisohexyl adipate, dihexyldecyl adipate, diisopropyl sebacate, lauryllactate, myristyl lactate, and cetyl lactate.

g. Alkenyl esters of fatty acids having 10 to 20 carbon atoms. Examplesthereof include oleyl myristate, oleyl stearate, and oleyl oleate.

h. Fatty acids having 9 to 22 carbon atoms. Suitable examples includepelargonic, lauric, myristic, palmitic, stearic, isostearic,hydroxystearic, oleic, linoleic, ricinoleic, arachidonic, behenic, anderucic acids.

i. Fatty alcohols having 10 to 22 carbon atoms. Lauryl, myristyl, cetyl,hexadecyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl,behenyl, erucyl, and 2-octyl dodecyl alcohols are examples ofsatisfactory fatty alcohols.

j. Fatty alcohol ethers. Ethoxylated fatty alcohols of 10 to 20 carbonatoms include the lauryl, cetyl, stearyl, isostearyl, oleyl, andcholesterol alcohols having attached thereto from 1 to 50 ethylene oxidegroups or 1 to 50 propylene oxide groups, or a mixture thereof.

k. Ether-esters such as fatty acid esters of ethoxylated fatty alcohols.

l. Lanolin and derivatives. Lanolin, lanolin oil, lanolin wax, lanolinalcohols, lanolin fatty acids, isopropyl lanolate, ethoxylated lanolin,ethoxylated lanolin alcohols, ethoxylated cholesterol, propoxylatedlanolin alcohols, acetylated lanolin, acetylated lanolin alcohols,lanolin alcohols linoleate, lanolin alcohols ricinoleate, acetate oflanolin alcohols ricinoleate, acetate of ethoxylated alcohols-esters,hydrogenolysis of lanolin, ethoxylated hydrogenated lanolin, ethoxylatedsorbitol lanolin, and liquid and semisolid lanolin absorption bases areillustrative of emollients derived from lanolin.

m. Polyhydric alcohols and polyether derivatives. Propylene glycol,dipropylene glycol, polypropylene glycol (M.W. 2000-4000),polyoxyethylene polyoxypropylene glycols, polyoxypropylenepolyoxyethylene glycols, glycerol, ethoxylated glycerol, propoxylatedglycerol, sorbitol, ethoxylated sorbitol, hydroxypropyl sorbitol,polyethylene glycol (M.W. 200-6000), methoxy polyethylene glycols 350,550,750, 2000, 5000, poly[ethylene oxide] homopolymers (M.W.100,000-5,000,000), polyalkylene glycols and derivatives, hexyleneglycol (2-methyl-2,4-pentanediol), 1,3-butylene glycol,1,2,6-hexanetriol, ethohexadiol USP (2-ethyl-1,3-hexanediol) C₁₅ -C₁₈vicinal glycol, and polyoxypropylene derivates of trimethylolpropane areexamples thereof.

n. Polyhydric alcohol esters. Ethylene glycol mono- and di-fatty acidesters, diethylene glycol mono- and di-fatty acid esters, polyethyleneglycol (M.W. 200-6000) mono- and di-fatty acid esters, propylene glycolmono- and di-fatty acid esters, polypropylene glycol 2000 monooleate,polypropylene glycol 2000 monostearate, ethoxylated propylene glycolmonostearate, glyceryl mono- and di-fatty acid esters, polyglycerolpoly-fatty acid esters, ethoxylated glyceryl monostearate, 1,3-butyleneglycol monostearate, 1,3-butylene glycol distearate, polyoxyethylenepolyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylenesorbitan fatty acid esters are satisfactory polyhydric alcohol esters.

o. Wax esters such as beeswax, spermaceti, myristyl myristate, stearylstearate.

p. Beeswax derivatives, e.g., polyoxyethylene sorbitol beeswax. Theseare reaction products of beeswax with ethoxylated sorbitol of varyingethylene oxide content, forming a mixture of ether-esters.

q. Vegetable waxes including carnauba and candelilla waxes.

r. Phospholipids such as lecithin and derivatives.

s. Sterols. Cholesterol, cholesterol fatty acid esters are examplesthereof.

t. Amides such as fatty acid amides, ethoxylated fatty acid amides,solid fatty acid alkanolamides.

The lotions further comprise from 1% to 10%, preferably from 2% to 5%,of an emulsifier. The emulsifiers can be nonionic, anionic or cationic.Examples of satisfactory nonionic emulsifiers include fatty alcoholshaving 10 to 20 carbon atoms, fatty alcohols having 10 to 20 carbonatoms condensed with 2 to 20 moles of ethylene oxide or propylene oxide,alkyl phenols with 6 to 12 carbon atoms in the alkyl chain condensedwith 2 to 20 moles of ethylene oxide, mono- and di-fatty acid esters ofethylene oxide, mono- and di-fatty acid esters of ethylene glycolwherein the fatty acid moiety contains from to 20 carbon atoms,diethylene glycol, polyethylene glycols of molecular weight 200 to 6000,propylene glycols of molecular weight 200 to 3000, glycerol, sorbitol,sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan andhydrophilic wax esters. Suitable anionic emulsifiers include the fattyacid soaps, e.g. sodium, potassium and triethanolamine soaps, whereinthe fatty acid moiety contains from 10 to 20 carbon atoms. Othersuitable anionic emulsifiers include the alkali metal, ammonium orsubstituted ammonium alkyl sulfates, alkyl arylsulfonates, an alkylethoxy ether sulfonates having 10 to 30 carbon atoms in the alkylmoiety. The alkyl ethoxy ether sulfonates contain from 1 to 50 ethyleneoxide units. Satisfactory cationic emulsifiers are the quaternaryammonium, morpholinium and pyridinium compounds. Certain of theemollients described in preceding paragraphs also have emulsifyingproperties. When a lotion is formulated containing such an emollient, anadditional emulsifier is not needed, though it can be included in thecomposition.

The balance of the lotion is water or a C₂ or C₃ alcohol, or a mixtureof water and the alcohol. The lotions are formulated by simply admixingall of the components together. Preferably the compound of the presentinvention is dissolved in the mixture. Conventional optional componentscan be included. One such additive is a thickening agent at a level from1% to 10% of the composition. Examples of suitable thickening agentsinclude: cross-linked carboxypolymethylene polymers, ethyl cellulose,polyethylene glycols, gum tragacanth, gum kharaya, xanthan gums andbentonite.

2. Creams

Compositions of this invention also can be formulated in a cream form.The creams comprise an effective amount (preferably from about 0.1% toabout 10%) of the compound of the present invention; from 5% to 50%,preferably from 10% to 25%, of an emollient; the balance being water.The emollients above described can also be used in the creamcompositions. Optionally the cream form contains a suitable emulsifier,as previously described. When an emulsifier is included, it is in thecomposition at a level from 3% to 50%, preferably from 5% to 20%.

3. Solutions

The compositions of this invention can be also formulated in a solutionform. The solution form comprises an effective amount (preferably fromabout 0.1% to about 10%) of the compound of the present invention; thebalance being water and/or a suitable organic solvent. Suitable organicmaterials useful as the solvent or a part of a solvent system are asfollows: propylene glycol, polyethylene glycol (M.W. 200-600),polypropylene glycol (M.W. 425-2025), glycerine, sorbitol esters,1,2,6-hexanetriol, ethanol, isopropanol, diethyl tartrate, butanediol,and mixtures thereof. Such solvent systems can also contain water.

These compositions in the solution form can be applied to the skin asis, or else can be formulated into an aerosol and applied to the skin asa spray-on. The aerosol compositions further comprise from 25% to 80%,preferably from 30% to 50%, of a suitable propellant. Examples of suchpropellants are the chlorinated, fluorinated and chlorofluorinated lowermolecular weight hydrocarbons. Nitrous oxide, carbon dioxide, butane,and propane are also used as propellant gases. These propellants areused at a level sufficient to expel the contents of the container.

4. Gels

Compositions herein can be formulated into a gel form by simply admixinga suitable thickening agent to the previously described solutioncompositions. Examples of suitable thickening agents have beenpreviously described with respect to the lotions.

The gelled compositions comprise an effective amount (preferably fromabout 0.1% to about 10%) of the compound of the present invention; from5% to 75%, preferably from 10% to 50%, of an organic solvent aspreviously described; from 0.5% to 20%, preferably from 1% to 10% of thethickening agent; the balance being water.

5. Solids

The compositions of this invention can also be formulated into a solidform. Such forms have use as a stick-type composition intended forapplication to the lips or other part of the body. Such compositionscomprise an effective amount (preferably from about 0.1% to about 10%)of the compound of the present invention and from 50% to 98%, preferablyfrom 60% to 90%, of the previously described emollients. Thiscomposition can further comprise from 1% to 20%, preferably from 5% to15%, of a suitable thickening agent, and optionally emulsifiers andwater. Thickening agents previously described with respect to lotionsare suitable herein.

Additives commonly found in topical compositions such as preservatives,e.g., methyl and ethyl-paraben, dyes and perfume can be included in anyof the previously described topical compositions.

The preferred dosage form for topical administration is a lotioncomprising a safe and effective amount of the analgesic agent of thepresent invention, which is preferably a concentration of from about0.01 mg/ml to about 10 mg/ml, more preferably from about 0.1 mg/ml toabout 5 mg/ml, and most preferably from about 0.5 mg/ml to about 2mg/ml. While topical application is preferably utilized to producelocalized analgesic effects, systemic effects can also be achieved byutilizing larger dosages of the topical compositions and/or greatersurface area coverage.

C. Injectable Dose Forms:

The compounds of the present invention are also useful when injected.The dosage of the compound of the present invention which is both safeand effective to provide analgesic or antiirritant activity will varywith the particular condition being treated, the severity of thecondition, the duration of treatment, the specific compound employed andits usage concentration, and like factors within the specific knowledgeand expertise of the attending physician and commensurate with areasonable benefit/risk ratio associated with the use of any drugcompound. In addition, lower dosages will be utilized when only localanalgesia is desired, whereas higher dosages will be utilized whengeneral analgesia is desired. The injectable dosages and dosage rangesgiven herein are based on delivery of the compound of the presentinvention to a 70 kg human and can be adjusted to provide equivalentdosages for patients of different body weights.

Methods and materials for manufacturing injectables can be found inRemington's Pharmaceutical Sciences, 17ed., 1985, Chapter 85, p. 1518,the disclosures of which are incorporated herein by reference in theirentirety. Materials for use in injectables are also described more fullyhereinafter.

Generally, three types of injectable dosage forms are preferred: 1)aqueous solutions; 2) non-aqueous solutions; and 3) emulsions. The abovedosage forms typically contain from about 0.001 mg/ml to about 10 mg/ml,preferably from about 0.1 mg/ml to about 1 mg/ml, more preferably fromabout 0.4 mg/ml to about 0.6 mg/ml.

The aqueous solutions preferably consist of water (preferably from about80% to about 90%), a suitable solubilizer, various types of acids, andan antimicrobial agent. Several solubilizers are known. Examples of suchsolubilizers are as follows: urea compounds (e.g., urea; urethan);surfactants (e.g., Tweens; Spans; sodium deoxycholate and Pluronics);cellulosic agents (e.g., carboxymethylcellulose); carbohydrates (e.g.,sorbitol; mannitol); B vitamins (e.g., nicotinamide); xanthinederivatives; and alcohols (e.g., benzyl alcohol). Examples of acids tobe used include the following: glucuronic; galacturonic; fumaric;gentisic; acetic; citric and lactobionic. Types of antimicrobial agentsthat can be used are the following: phenylmercuric nitrate; thimerosal;benzethonium chloride; benzalkonium chloride; phenol; cresol; andchlorobutanol. An art-known local anesthetic (e.g., benzyl alcohol;Novocaine®; lidocaine) may also be included.

Non-aqueous solutions can comprise solvents which are either misciblewith water or immiscible with water. Non-aqueous solvents miscible withwater are mixed with water to yield a concentration preferably betweenfrom about 5% to about 90%. Examples of typical non-aqueous solventsmiscible with water include: solvents used at 100% (e.g., propyleneglycol; polyethylene glycol; dimethylformamide; dimethylacetamide);solvents mixed with water to yield a concentration of between from about5% to about 90% (e.g., ethanol; glycerin; butylene glycol; tetraglycol;dimethylacetamide; dimethylformamide; lactic acid; ethyl acetate;N-B-hydroxyethyl lactamide; tetraethylurea; acetone; sulfolane;isopropylene glycol ether; hexenyl glycol; diethylene glycol dimethylether; tetrahydrofurfuryl methyl ether; N,N-dimethylmethoxyacetamide).

Non-aqueous solvents not miscible with water are primarily vegetableoils. Some common lipid solvents not miscible with water for injectablecompositions are sesame oil, olive oil, arachis oil, maize oil, almondoil, cottonseed oil, castor oil, ethyl oleate, ethyl carbonate andisopropyl myristate.

Emulsions can be of either the water-in-oil (W/O) or the oil-in-water(O/W) type. Typical oils are listed hereinbefore. The continuous phaseis preferably about 99% of the formulation while the discontinuous phaseis preferably about 1% of the formulation. Emulsifiers and stabilizersare typically used to complete the formulation. Examples of typicalemulsifying agents are: surface active agents (e.g., sodiumdeoxycholate; Span; Tween); and natural surface active agents (e.g.,Sorbit; phosphatidylcholine).

Injectable dose forms for producing general analgesia typically comprisefrom about 0.1 mg to about 1000 mg, and preferably from about 0.5 of toabout 700 mg, of the compound of the present invention. Injectable doseforms for producing local analgesia typically comprise from about 1 ugto about 500 ug of the compound of the present invention.

Methods for Producing Anti-Inflammatory Activity and Analgesia

The present invention also encompasses methods of producinganti-inflammatory activity and/or analgesia (either general analgesia orlocal analgesia) in humans or lower animals through administering, tothe human or lower animal in need of such treatment, a safe andeffective amount of a compound of the present invention. This amount canbe given in a single dose or multiple doses repeatedly over the courseof the treatment. While dosages higher than those described hereinbeforeare effective to reduce inflammation and produce analgesia, care must betaken in some individuals to prevent adverse side effects. The compoundsand compositions of this invention can be used to treat and preventpain, to provide analgesia, and/or to reduce inflammation in variousdisorders at the deeper structures, muscles, tendons, bursa and jointsassociated with disease and trauma, and in various other conditions inwhich non-steroidal anti-inflammatory, antipyretic and analgesic drugs,such as aspirin, and opioids, such as morphine, have heretofore beenused to alleviate pain and discomfort and reduce inflammation.

The preferred modes of administration are orally, topically, and byinjection, including, e.g., dermatomucosally (for example, dermally,rectally and the like) and parenterally (for example, by subcutaneousinjection, intramuscular injection, intra-articular injection,intravenous injection and the like). Ocular administration andinhalation is also included. Thus, specific modes of administrationinclude, without limitation, oral, transdermal, mucosal, sublingual,intramuscular, intravenous, intraperitoneal, and subcutaneousadministration, as well as topical application.

The phrase "safe and effective amount", as used herein, means an amountof a compound or composition high enough to significantly positivelymodify the condition to be treated, but low enough to avoid serious sideeffects (at a reasonable benefit/risk ratio), within the scope of soundmedical judgment. The safe and effective amount of the compound orcomposition will vary with the particular condition being treated, theage and physical condition of the patient being treated, the severity ofthe condition, the duration of the treatment, the nature of concurrenttherapy, the specific analgesic agent employed, the particularpharmaceutically-acceptable carrier utilized, whether general or localanalgesia is desired, and like factors within the knowledge andexpertise of the attending physician. However, daily dosages can rangefrom about 0.1 mg/kg of body weight to about 500 mg/kg of body weight.Preferred daily dosages are from about 1 to about 100 mg/kg of bodyweight. Up to about 6 single dosages per day may be administered.

Topical administration can be used to reduce inflammation and producelocal or systemic analgesia, through directly laying on or spreading asafe and effective amount of the compound or composition of the presentinvention on epidermal or epithelial tissue, including outer skin andoral, gingival, and nasal tissue. The amount of the pharmaceuticalcomposition to be topically administered may vary from about 0.01 mg/cm²to 5 mg/cm², and if a patch is worn over the affected area possiblyhigher concentrations, depending upon such factors as the sensitivity,type and location of tissue to be treated, the composition and carrier(if any) to be administered, and the particular compound to beadministered as well as the particular disorder to be treated and theextent to which systemic (as distinguished from local) effects aredesired. The extent of systemic analgesia also depends upon such factorsas the amount of compound, the area of tissue to be covered, and theability of the compound to penetrate the skin tissue.

Oral administration can be used to reduce inflammation and produceanalgesia through oral dosing of a pharmaceutical composition comprisedof a safe and effective amount of the compound of the present inventionin a suitable oral pharmaceutical carrier. The compound is absorbed bythe gastrointestinal tract. The pharmaceutical composition may consistof solid dosage forms such as tablets, hard gelatin capsules, softgelatin capsules, bulk powders, and microcapsules of the drug.Alternately, it may consist of a liquid dosage form such as an aqueousor nonaqueous solution, emulsion, or suspension.

The amount of the compound ingested depends upon the bioavailability ofthe compound from the oral pharmaceutical composition. Typically,however, the compounds of the present invention are dosed in an amountof from about 0.1 mg/kg of body weight to about 500 mg/kg, andpreferably from about 1 to about 100 mg/kg of body weight. The amount ofthe pharmaceutical composition depends upon the percent of compoundwithin its formula, which is a function of the amount of the compoundrequired per dose, its stability, release characteristics and otherpharmaceutical parameters. Generally, the oral pharmaceuticalcomposition should comprise from about 5% to about 50% of the compoundof the present invention.

The preferred method of injectable administration is via a sterileaqueous solution of pH from about 3 to about 8 (more preferred is pH offrom about 3 to about 6) or as a sterile emulsion. Larger amounts ofdrug can be administered to produce systemic analgesia using doses inthe range of 0.01 to 10.0 mg/kg; however, smaller amounts of the drugcan be administered via injection to produce a local analgesic and/oranti-inflammatory effect. The smaller quantities of drug to beadministered are typically in the range of from about 1 to about 500ug/injection; these amounts are used to produce a local analgesic effectwithout the numbing affect commonly associated with a local anesthetic.Such low doses avoid any significant systemic exposure to the drug andthereby greatly reduce the possibility of side effects. These localadministrations may be useful for the treatment of pain and inflammationassociated with minor surgical procedures, e.g., minor oral surgeries,tooth extractions, etc., or minor orthopedic surgeries. The preferredmodes of administration for producing local analgesia are interdermally,subcutaneously, percutaneously, and intramuscularly.

Systemic administration can also be used to reduce inflammation andproduce general analgesia. Such administration may be intravenously,intramuscularly, or subcutaneously. The amount of pharmaceuticalcomposition typically administered may vary from about 0.5 to about 5 mlof a solution or suspension of the compound of the present invention ina pharmaceutically-acceptable carrier in a single dose. Thesecompositions may also be administered systemically in multiple dosages,or by infusion.

Methods for Synthesizing Compounds of the Present Invention

The present invention also encompasses methods for synthesizing theanalgesic and/or anti-inflammatory agents of the present invention.These novel methods are useful for synthesizing these compounds in highyield and/or at low cost.

a) Azide Reduction Synthesis Method

This novel method for preparing beta-aminoethoxy-substituted phenylcompounds of the present invention provides a low cost and high yieldroute to obtaining these compounds. This method comprises the steps of:

(1) reacting, to form a beta-haloethoxy phenyl compound:

(a) a phenol compound having the structure: ##STR32## wherein: the--W--X-- moiety is selected from the group consisting of --C(O)NH--,--C(S)NH--, --S(O)₂ NH--, --NHC(O)O--, --NHC(S)O--, --NHC(O)NH-- and--NHC(S)NH-- wherein either available bond of the --W--X-- moiety isbonded to the --R moiety and the remaining bond is attached to thebenzyl carbon atom; --Z is selected from the group consisting ofhydrogen, hydroxy, and methoxy; --R is an alkyl group having from about6 to about 24 carbon atoms; --R¹ is selected from the group consistingof hydrogen, hydroxy, alkyl esters of hydroxy having from about 1 toabout 5 carbon atoms, alkyl having from about 1 to about 5 carbon atoms,and alkoxy having from about 1 to about 5 carbon atoms; and

(b) a vicinal dihalide having the structure:

X--CR² ₂ CR² ₂ --X

wherein: X is halogen; and each --R² is independently selected fromhydrogen, halogen, unsubstituted or substituted alkyl having from about1 to about 5 carbon atoms, substituted or unsubstituted aryl, andcarboxylate, or two --R² moieties are covalently bonded to form asubstituted or unsubstituted alkyl ring having from about 3 to about 7carbon atoms in the ring; followed by

(2) reacting the beta-haloethoxy phenyl compound with an azide salt(e.g., sodium azide; potassium azide) to form a beta-azidoethoxy phenylcompound; followed by

(3) reducing the azido moiety to an amino moiety to form thebeta-aminoethoxy phenyl compound.

Preferably, this method comprises the steps of (1) reacting the phenolcompound with a vicinal dibromide having the structure Br--CR² ₂ CR² ₂--Br to form a beta-bromoethoxy phenyl compound; followed by (2)reacting the beta-bromoethoxy phenyl compound with an azide salt to forma beta-azidoethoxy phenyl compound; followed by (3) reducing the azidomoiety to an amino moiety with SnCl₂ to form the beta-aminoethoxy phenylcompound.

This preferred azide reduction method of the present invention generallyinvolves the following reaction scheme: ##STR33##

The phenol starting materials for this synthesis method are knowncompounds disclosed, for example, in the references incorporatedhereinbefore by reference. The vicinal dihalides, particularly vicinaldibromides (e.g., 1,2-dibromoethane), are known compounds which areeither commercially available or readily synthesized by art-knownmethods such as are disclosed, for example, in Morrison and Boyd,Organic Chemistry, Third Edition (Allyn and Bacon, Inc., Boston; 1973)pp. 186-187 and pp. 197-199, the disclosures of which are incorporatedherein by reference in their entirety. The use of this method tosynthesize compounds of the present invention is described more fully inthe Examples hereinafter.

The present invention further relates to the novel betahaloethoxy phenylcompounds and beta-azidoethoxy phenyl compounds which are usefulintermediates in this synthesis method. These substituted phenylcompounds have the general structure: ##STR34## wherein: the --W--X--moiety is selected from the group consisting of --C(O)NH--, --C(S)NH--,--S(O)₂ NH--, --NHC(O)O--, --NHC(S)O--, --NHC(O)NH-- and --NHC(S)NH--wherein either available bond of the --W--X-- moiety is bonded to the--R moiety and the remaining bond is attached to the benzyl carbon atom;--A is selected from the group consisting of halogen and --N₃ ; --Z isselected from the group consisting of hydrogen, hydroxy, and methoxy;--R is an alkyl group having from about 6 to about 24 carbon atoms; --R¹is selected from the group consisting of hydrogen, hydroxy, alkyl estersof hydroxy having from about 1 to about 5 carbon atoms, alkyl havingfrom about 1 to about 5 carbon atoms, and alkoxy having from about 1 toabout 5 carbon atoms; and each --R² is independently selected fromhydrogen, halogen, unsubstituted or substituted alkyl having from about1 to about 5 carbon atoms, substituted or unsubstituted aryl, andcarboxylate, or two --R² moieties are covalently bonded to form asubstituted or unsubstituted alkyl ring having from about 3 to about 7carbon atoms in the ring. The preferred W, X, --Z, --R, --R¹, and --R²groups are as described hereinbefore for the beta-aminoethoxy phenylcompounds. Most preferred is --R¹ being hydrogen, --Z being methoxy,--W--X-- being --C(O)NH--, and --A being bromine or --N₃. Representativecompounds are described in the Examples hereinafter.

b) Phthalimide Synthesis Method

This novel method for preparing beta-aminoethoxy-substituted phenylcompounds of the present invention provides a low cost and high yieldroute to obtaining these compounds. This method comprises the steps of:

(1) reacting, to form a beta-haloethoxy phenyl compound:

(a) a phenol compound having the structure: ##STR35## wherein: the--W--X-- moiety is selected from the group consisting of --C(O)NH--,--C(S)NH--, --S(O)₂ NH--, --NHC(O)O--, --NHC(S)O--, --NHC(O)NH-- and--NHC(S)NH-- wherein either available bond of the --W--X-- moiety isbonded to the --R moiety and the remaining bond is attached to thebenzyl carbon atom; --Z is selected from the group consisting ofhydrogen, hydroxy, and methoxy; --R is an alkyl group having from about6 to about 24 carbon atoms; --R¹ is selected from the group consistingof hydrogen, hydroxy, alkyl esters of hydroxy having from about 1 toabout 5 carbon atoms, and alkoxy having from about 1 to about 5 carbonatoms; and

(b) a vicinal dihalide having the structure:

X--CR² ₂ CR² ₂ --X

wherein: X is halogen; and each --R² is independently selected fromhydrogen, halogen, unsubstituted or substituted alkyl having from about1 to about 5 carbon atoms, substituted or unsubstituted aryl, andcarboxylate, or two --R² moieties are covalently bonded to form asubstituted or unsubstituted alkyl ring having from about 3 to about 7carbon atoms in the ring; followed by

(2) reacting the beta-haloethoxy phenyl compound with a phthalimide salt(e.g. potassium phthalimide) to form a beta-phthalimidoethoxy phenylcompound; followed by

(3) reacting the beta-phthalimidoethoxy phenyl compound with hydrazineto remove the phthalimido group and form the beta-aminoethoxy phenylcompound.

Preferably, this method comprises the steps of (1) reacting the phenolcompound with a vicinal dibromide having the structure Br--CR² ₂ CR² ₂--Br to form a beta-bromoethoxy phenyl compound; followed by (2)reacting the beta-bromoethoxy phenyl compound with an phthalimide saltto form a beta-phthalimidoethoxy phenyl compound; followed by (3)reacting the beta-phthalimidoethoxy compound with NH₂ NH₂ to form thebeta-aminoethoxy phenyl compound. This preferred phthalimide synthesismethod of the present invention generally involves the followingreaction scheme: ##STR36##

The phenol starting materials for this synthesis method are knowncompounds disclosed, for example, in the references incorporatedhereinbefore by reference. The vicinal dihalides, particularly vicinaldibromides (e.g., 1,2-dibromoethane), are known compounds which areeither commercially available or readily synthesized by art-knownmethods such as are disclosed, for example, in Morrison and Boyd,Organic Chemistry, Third Edition (Allyn and Bacon, Inc., Boston; 1973)pp. 186-187 and pp. 197-199, the disclosures of which are incorporatedherein by reference in their entirety. The use of this method tosynthesize compounds of the present invention is described more fully inthe Examples hereinafter.

The present invention further relates to the novelbeta-phthalimidoethoxy phenyl compounds which are useful intermediatesin this synthesis method. These substituted phenyl compounds have thegeneral structure: ##STR37## wherein: the --W--X-- moiety is selectedfrom the group consisting of --C(O)NH--, --C(S)NH--, --S(O)₂ NH--,--NHC(O)O--, --NHC(S)O--, --NHC(O)NH-- and --NHC(S)NH-- wherein eitheravailable bond of the --W--X-- moiety is bonded to the --R moiety andthe remaining bond is attached to the benzyl carbon atom; --A isselected from the group consisting of halogen and phthalimide; --Z isselected from the group consisting of hydrogen, hydroxy, and methoxy;--R is an alkyl group having from about 6 to about 24 carbon atoms; --R¹is selected from the group consisting of hydrogen, hydroxy, alkyl estersof hydroxy having from about 1 to about 5 carbon atoms, alkyl havingfrom about 1 to about 5 carbon atoms, and alkoxy having from about 1 toabout 5 carbon atoms; and each --R² is independently selected fromhydrogen, halogen, unsubstituted or substituted alkyl having from about1 to about 5 carbon atoms, substituted or unsubstituted aryl, andcarboxylate, or two --R² moieties are covalently bonded to form asubstituted or unsubstituted alkyl ring having from about 3 to about 7carbon atoms in the ring. The preferred W, X, --Z, --R, --R¹, and --R²groups are as described hereinbefore for the beta-aminoethoxy phenylcompounds. Most preferred is --R¹ being hydrogen, --Z being methoxy,--W--X-- being --C(O)NH--, and --A being bromine or phthalimide.Representative compounds are described in the Examples hereinafter.

c) Aziridine Synthesis Method

This novel method for preparing beta-aminoethoxy-substituted phenylcompounds of the present invention provides a high yield route toobtaining these compounds. The method comprises the steps of:

(1) reacting, to form a nitrogen-substituted beta-aminoethoxy phenylcompound:

(a) a phenol compound having the structure: ##STR38## wherein: the--W--X-- moiety is selected from the group consisting of --C(O)NH--,--C(S)NH--, --S(O)₂ NH--, --NHC(O)O--, --NHC(S)O--, --NHC(O)NH-- and--NHC(S)NH-- wherein either available bond of the --W--X-- moiety isbonded to the --R moiety and the remaining bond is attached to thebenzyl carbon atom; --Z is selected from the group consisting ofhydrogen, hydroxy, and methoxy; --R is an alkyl group having from about6 to about 24 carbon atoms; and --R¹ is selected from the groupconsisting of hydrogen, hydroxy, alkyl esters of hydroxy having fromabout 1 to about 5 carbon atoms, alkyl having from about to about 5carbon atoms, and alkoxy having from about 1 to about 5 carbon atoms;

(b) an aziridine compound having the structure: ##STR39## wherein each--R² is independently selected from hydrogen, halogen, unsubstituted orsubstituted alkyl having from about 1 to about 5 carbon atoms,substituted or unsubstituted aryl, and carboxylate, or two --R² moietiesare covalently bonded to form a substituted or unsubstituted alkyl ringhaving from about 3 to about 7 carbon atoms in the ring; followed by

(2) reducing the nitrogen substituent off of the nitrogen-substitutedbeta-aminoethoxy phenyl compound to form the beta-aminoethoxy phenylcompound.

Preferably, this method comprises the steps of: (1) reacting the phenolcompound as its phenolic anion with the aziridine compound; followed by(2) reducing the nitrogen substituent off of the nitrogen-substitutedbeta-aminoethoxy phenyl compound with sodium metal in liquid ammonia.

This preferred aziridine synthesis method of the present inventiongenerally involves the following reaction scheme: ##STR40##

The phenol compounds which are the starting materials for the aziridinesynthesis method are readily synthesized by artknown methods asdescribed hereinbefore. The aziridine compounds are readily synthesizedby art-known methods, for example, as described in March, AdvancedOrganic Chemistry, 3rd Edition (J. Wiley & Sons, New York; 1985), p.325; and are readily converted to the N-(para-toluenesulfonyl)-aziridinecompound by simple reaction of the aziridine with para-toluenesulfonylchloride. The use of this method to synthesize representative compoundsof the present invention is described more fully in the Exampleshereinafter.

The following Examples further describe and demonstrate the preferredembodiments within the scope of the present invention. The Examples aregiven solely for the purpose of illustration, and are not to beconstrued as limitations of the present invention since many variationsthereof are possible without departing from its spirit and scope. Alltemperature readings are in °C.

EXAMPLE I Synthesis ofN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)nonanamide ##STR41##

To a flame dried 5L, 3 neck, round bottom flask is addedN-vanillylnonanamide (20.9 g; 71.3 millimole; which is disclosed in U.S.Pat. No. 4,313,958, to LaHann, issued Feb. 2, 1982, incorporated byreference in its entirety herein), hexamethylphosphoramide (49.65 mL)and 2830 mL of dimethylformamide. After dissolving at room temperaturewith mechanical stirring, potassium tert-butoxide (28 g; 249.7millimole) is added with stirring. A solution containing(N-trifluoroacetyl)-2-bromo-aminoethane (17.3 g; 78.5 millimole) in 170mL of dimethylformamide is added dropwise over a period of 1 hour to themixture described above with continuous stirring. The reaction mixtureis then heated to 80° C. in an oil bath for 18 hours, after which timeit is allowed to cool to room temperature. The reaction mixture is thenconcentrated to a volume of approximately 200 mL under vacuum. Theconcentrated residue is diluted to 6L with diethyl ether and washedsuccessively with 2×4 L of 0.5 N HCl, 2×4 L of water, and 500 mL ofsaturated sodium chloride. The ether layer is dried over magnesiumsulfate and evaporated to a white solid. The white solid product isrecrystallized from ether to yield 10.07 g of the desired productN-((4-(2-(N'-trifluoroacetyl)-aminoethoxy)3-methoxyphenyl)-methyl)-nonanamide(yield 32%).

TheN-((4-(2-(N'-trifluoroacetyl)-aminoethoxy)-3-methoxy-phenyl)-methyl)-nonanamide(10.07 g) is dissolved in 400 mL of ethanol, and 23.2 mL of 2.5 N sodiumhydroxide is added. The reaction is stirred at room temperature for 2hours and then diluted with 2 L of water. The aqueous mixture isextracted with ethyl acetate (4×500 mL), and the ethyl acetate extractsare combined, washed with saturated sodium chloride, and dried overanhydrous sodium sulfate. The ethyl acetate solution is concentrated toyield 7.7 g of solid product which is purified as follows.

The crude product is dissolved in 70 mL of warm chloroform and loadedonto a silica gel column. The column is eluted under reduced presure(aspirator) with 2700 mL of chloroform and the eluant is discarded. Thecolumn is then eluted with 1500 mL of a solvent mixture containingchloroform 93%, triethylamine 2%, and methanol 5%. This second eluant iscollected, concentrated, and then dried to yield 6.86 g of white solidproduct N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanamide (yield88%). m.p.=118-119° C.; ¹ H-NMR (CDCl₃): 0.97 (3H, t), 1.2-2.0 (14H, m),2.25 (2H, t), 3.17 (2H, t), 3.9 (3H, s), 4.15 (2H, t), 4.45 (2H, d), 6.0(1H, m), 6.85 (3H, br s, aromatic).

Starting with the compound N-oleyl-4-hydroxy-3-methoxyphenylacetamide(which is disclosed in European Patent Application Publication No.206,609, Berman et al., published Dec. 30, 1986, the disclosures ofwhich are incorporated herein by reference in their entirety) and usingsubstantially the same method as described hereinbefore, the compoundN-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide isprepared. ¹ H NMR (CDCl₃): 0.9 (3H, t), 1.25 (br s, 24H), 1.75 (s, 2H),1.8-2.1 (m, 4H), 3.0-3.25 (m, 4H), 3.5 (s, 2H), 3.85 (s, 3H), 4.05 (t,2H), 5.2-5.6 (m, 3H), 6.9 ppm (br s, 3H).

EXAMPLE II Synthesis ofN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide by theAzide Reduction Method ##STR42## (a) Synthesis ofN-((4-(2-bromoethoxy)-3-methoxyphenyl)methyl)-9Z-octadecenamide:

N-vanillyloleamide (100 gm, 0.24 mole; which is prepared as described inU.S. Pat. No. 4,493,848 to LaHann and Buckwalter, issued Jan. 15, 1985),1,2-dibromoethane (500 ml), 40% KOH (165 ml) and 40% tetrabutylammoniumhydroxide (15 ml) are combined in a 2 L flask equipped with athermometer, mechanical stirrer and reflux condenser, and the solutionis heated to 55° C. The disappearance of starting material is monitoredby TLC (6% acetone/CH₂ Cl₂). After the reaction is completed (typicallyafter reacting overnight), the solution is diluted with CHCl₃ (500 ml),washed three times with water and the aqueous washings are then combinedand extracted once with CHCl₃ (250 ml). The organic phases are combined,washed with 10% H₃ PO₄ (250 ml), saturated NaHCO₃ (250 ml), brine, thendried (MgSO₄) and filtered. The volume is reduced to less than 500 ml byvacuum distillation and the liquid is then transferred to a 4-L flask.After cooling to approximately 10° C., Et₂ O (2L) is added and the flaskis cooled in an ice bath. A white precipitate forms and additional Et₂ Ois added to make a volume of 4 l. The thick amorphous solid is filtered,washed with Et₂ O, dried and used without further purification.Mp=96°-97° C. ¹ H NMR (CDCl₃) (ppm): 6.8 (s, 3H), 5.9 (m, 1H), 5.3 (t,2H J=5Hz), 4.3 (m, 4H), 3.8 (s, 3H), 3.6 (t, 2H, J=6 5 Hz), 2.3-2.1 (m,4H), 2.0-1.5 (m, 2H), 1.2 (s, 22H), 0.85 (t, 3H). ¹³ C NMR (CDCl₃)(ppm): 14.0, 22.5, 25.6, 27.0, 29.1, 31.7, 36.5, 43.0, 55.8, 69.3,111.9, 115.0, 119.8, 129.5, 132.8, 146.5, 149.8, 172.8.

(b) Synthesis ofN-((4-(2-azidoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide:

N-((4-(2-bromoethoxy-3-methoxyphenyl)-methyl)-9Z-octadecenamide (182.0gm, 0.347 mole), sodium azide (100 gm, 1.54 mole), tetrabutylammoniumhydrogen sulfate (12.0 gm, 0.035 mole) and benzene (600 ml) are combinedin a 2 L flask equipped with a thermometer, mechanical stirrer andreflux condenser. The solution is heated to a gentle reflux for 24hours. The solution is transferred to a 6 L separatory funnel using 2 Lof EtAc to wash the inorganic residue. The solution is then extractedwith water (2 L), 10% H₃ PO₄ (1 L), saturated NaHCO₃ (1 L), dried(MgSO₄) and concentrated to give 156 gm (92%) of a white solid.Purification is accomplished using a Waters prep 500 HPLC (two columns)eluting with CHCl₃ to give 146 gm (86%) of pure azide. Mp=71°-73° C. ¹ HNMR (CDCl₃) (ppm): 6.8 (s, 3H), 6.1 (m, 1H), 5.3 (t, 2H, J=4.5), 4.3 (d,2H, J=5.5), 4.1 (t, 2H, J=5), 3.8 (s, 3H), 3.5 (t, 2H, J=5), 2.2-1.5 (m,4H), 1.4 (m, 2H), 1.3 (s, 22H), 0.84 (t, 3H). ¹³ C NMR (CDCl₃) (ppm):172.9, 150.0, 147.0, 132.7, 129.6, 119.8, 114.6, 111.9, 68.3, 55.8,50.1, 43.1, 36.6, 31.8, 29.1, 27.1, 25.7, 22.5, 14.0.

(c) Synthesis ofN-((4-(2-aminoethoxy)-3-methoxyphenyl)methyl)-9Z-octadecenamide:

N-((4-(2-azidoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide (139gm, 0.286 mole) is added to MeOH (1 L) in a 2 L flask. The mixture iswarmed to dissolve all the substrate. Stannous chloride dihydrate (97gm, 0.43 mole) is ground in a mortar and pestle and delivered all atonce to the reaction solution. The flask is then fitted with a shortVigreux column and a bubbler to monitor gas evolution. The paleyellow-green solution warms and gives a steady evolution of gas for 20minutes. The reaction is stirred a total of one hour. The content of thereaction vessel is poured into a 2 L graduated cylinder and fresh MeOHis added until the volume is 2 L. One-half of this solution is worked upat a time. 1 L of the reaction solution is placed in a 6 L separatoryfunnel and 1 N NaOH (1 L) is added, immediately forming a thickcheese-like precipitate. Na₂ SO₄ (50 gm) is added and the mixture isvigorously shaken for five minutes. To the suspension is added EtAc (2L) and the solution shaken until two layers form. 1200 ml of the aqueousphase is removed, H₂ O (500 ml) is added and the solution is reshaken.The aqueous layers are then combined and extracted with EtAc (1 L). Allthe organic layers are combined, dried (MgSO₄), filtered andconcentrated to give 125 gm (95%) of white solid. Purification isaccomplished on a Waters Prep 500 HPLC (2 columns) by firstequilibrating and eluting with CHCl₃ until nonpolar impurities areremoved (8 L CHCl₃), then by eluting with CHCl₃ /MeOH/triethylamine(94:3:3; 4L). The various fractions are analyzed by TLC usingbutanol/acetic acid/H₂ O (4:1:1); ninhydrin is used to develop theproduct spots. Yield=93 gm (70%). ¹ H NMR (CDCl₃) (ppm): 6.7 (s, 3H),6.1 (m, 1H), 5.3 (t, 2H), 4.3 (d, 2H), 3.9 (t, 2H), 3.8 (s, 3H), 3.0 (t,2H), 2.3-1.9 (m, 4H), 1.7-1.5 (m, 2H), 1.4 (s, 2H), 1.2 (s, 22H), 0.8(t, 3H). ¹³ C NMR (CDCl₃) (ppm): 172.8, 149.6, 131.8, 129.7, 119.9,113.8, 111.6, 71.6, 55.7, 43.1, 41.4, 36.6, 31.7, 29.1, 27.1, 25.6,22.5, 14.0.

EXAMPLE III Synthesis ofN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide by thePhthalimide Synthesis Method ##STR43## (a) Synthesis ofN-((4-(2-bromoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide isaccomplished following the same procedure as described in Example II.(b) Synthesis ofN-((4-(2-phthalimidoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide:

N-((4-(2-bromoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide (615.5gm, 1.17 moles) and DMF are combined in a 5 L flask equipped with amechanical stirrer and a thermometer. The mixture is stirred and heatedto 55° C. Once the solution becomes homogeneous, potassium phthalimide(270.0 gm, 1.47 mole) is added and the solution is maintained at 55° C.with good stirring. After ca. 10 minutes the reaction solution becomeshomogeneous. Precipitation of a white solid then begins and the reactionis allowed to stir overnight at 55° C. TLC (acetone/dichloromethane6:94) indicates when the starting material has been consumed. Thereaction solution is divided into three equal volumes and each is workedup as follows: The solution is poured into a 4 L beaker and then dilutedwith water to the 3500 mL mark. After standing for ca. 15 minutes thesolution is divided again into two equal parts, each of which is dilutedto 3500 mL with water. The white precipitate is removed by filtrationand washed several times with water. The three portions are combined anddried in a vacuum oven at 90° C. for 12 hours to give 682.25 g (98%) ofa fine powder. Mp 109.5°-111.0° C. ¹ H NMR (CDCl₃)(ppm): 7.8 (m, 4H),6.8 (m, 3H), 5.8 (m, 1H), 5.3 (t, 2H), 4.3 (d, 2H), 4.2 (t, 2H), 4.1 (t,2H), 3.7 (s, 3H), 2.2-2.0 (m, 4H), 1.6 (m, 2H), 1.2 (s, 22H), 0.9 (t,3H). ¹³ C NMR (CDCl₃)(ppm): 172.8, 167.9, 150.0, 147.1, 133.9, 132.5,132.1, 129.7, 123.1, 120.0, 114.9, 112.0, 66.2, 55.7, 43.2, 37.1, 36.7,31.8, 29.3, 27.1, 25.7, 22.6, 14.0. IR (cm-¹): 3300, 1775, 1715, 1635,1265, 1230, 1145, 1035, 1025, 720, CI-DEP Mass spectrum (m/z): 591(MH+).

(c) Synthesis ofN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide:

N-((4-(2-phthalimidoethoxy)-3-methoxyphenyl-methyl)-9Z-octadecenamide(250 gm, 0.424 mole) and ethanol (2500 mL) are combined in a 4 L beaker.The slurry is mechanically stirred and heated to 60° C. At ca. 45° C.the solution becomes homogeneous. 1-Hexene (20 mL) is added. Hydrazinehydrate (106 mL of a 64% aqueous solution) is then added. In ca. 5minutes a white precipitate begins to form. During the 2 hour reactiontime 500 mL of ethanol is added to the reaction to replenish that volumelost to evaporation. The reaction solution is then divided into threeequal portions and each is worked up as follows: Methyl t-butyl ether(1.5 L) is used to transfer the slurry into a 4 L separatory funnel.Water L) and IN NaOH (500 mL) are added and the solution is thoroughlyshaken. 50% NaOH (25 mL) is added and the solution is reshaken. Theorganic phase is then extracted twice with alkali using the samesequence, and washed with brine. The extract is dried over sodiumsulfate and concentrated. The crude product is taken up in hot methylt-butyl ether and allowed to crystallize. The crystals are filtered anddried in a vacuum desicator to give 124.87 g. A second crop of crystals,40.82 g, is obtained to give 85% total yield. Mp 102-106° C. ¹ H NMR(CDCl₃)(ppm): 6.7 (s, 3H), 6.1 (m, 1H), 5.3 (t, 2H), 4.3 (d, 2H), 3.9(t, 3H), 3.8 (s, 3H), 3.0 (t, 2H), 2.5 (s, 2H), 2.1-1.6 (m, 4H), 1.5-1.2(m, 2H), 1.2 (s, 22H), 0.9 (t, 3H). ¹³ C NMR (CDCl₃)(ppm): 172.9, 149.3,147.2, 131.8, 129.6, 119.7, 113.5, 111.4, 70.9, 55.5, 42.9, 40.9, 36.4,31.6, 29.0, 26.9, 25.6, 22.4, 13.8. IR max (cm⁻¹): 3380, 3300, 1630,1375, 1255, 1235, 1020, 800, 720 cm⁻¹. CI-DEP Mass Spectrum (m/z): 461(MH+).

EXAMPLE IV Synthesis ofN-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide by the Aziridine Method ##STR44##

To a solution of 2,2-dimethylaziridine (5.42 g; 0.076 mole; sold byPolysciences, Inc., Warrington, PA) in pyridine (100 mL) cooled in anice bath, is added p-toluenesulfonyl chloride (21.81 g; 0.114 mole) inone portion. The reaction is stirred at 0° C. for 2 hours; diluted withether (400 mL); washed with cold 10% H₃ PO₄ (2×150 mL), with a saturatedNaHCO₃ solution (3×150 mL) and brine (1×150 mL); and dried over MgSO₄.Rotary evaporation of the solution affords a yellowish solid which iscrystallized from ethyl acetate to yield the product2,2-dimethyl-N-p-toluenesulfonyl-aziridine (4.48 g). ¹ H NMR(CDCl₃):1.53 (6H, s), 2.45 (5H, m), 7.2-8.0 ppm (4H, m, aromatics).

A dispersion of KH (35% in oil; 68 mg; 0.595 mmole) is added to a dryround-bottom flask under argon and washed with n-pentane (3×5 mL) toremove the oil. The isolated KH is then suspended in dry DMF (5 mL) andtreated in one portion with N-vanillyloleamide (248 mg; 0.595 mmole;which is prepared as described in U.S. Pat. No. 4,493,848, to LaHann andBuckwalter, issued Jan. 15, 1985, incorporated herein by reference inits entirety) and stirred for 1 hour at room temperature. The2,2-dimethyl-N-p-toluenesulfonyl-aziridine (136 mg; 0.60 mmole) is thenadded and the resulting mixture is stirred at 50° C. for 16 hours. TheDMF is rotary evaporated and the residue partitioned between water andethyl acetate (50 mL). The organic layer is washed with water (4×20 mL),dried over MgSO₄ and rotary evaporated to yield a light brown oil (400mg) which is purified by using silica gel chromatography (Chromatotron,2 mm plate, eluting with 40% ethyl acetate/hexanes) to yield thep-toluenesulfonamido-blocked intermediate as a colorless oil, (140 mg;40%). ¹ H NMR (CDCl₃): 0.93 (3H, t), 1.30 (29H, m), 2.05 (6H, m), 2.42(3H, s), 3.65 (2H, s), 3.86 (3H, s), 4.38 (2H, d), 5.37 (2H, t), 5.7(1H, s), 6.00 (1H, br s), 6.77 (3H, m, aromatics), 7.1-7.8 ppm (4H, m,tosyl aromatics).

A solution of the p-toluenesulfonamido-blocked intermediate (2.46 g; 3.8mmoles) in dry THF (10 mL) is stirred at -60° C. under argon and treatedwith freshly condensed NH₃ until a final volume of 20 mL is achieved.This solution is then allowed to reflux gently under a dry ice condenserwhile small flakes of freshly cut sodium are slowly added. When a bluecolor persists for more than 5 minutes without the addition of moresodium, the reaction is quenched by the addition of solid ammoniumacetate and evaporated under a gentle stream of nitrogen. The remainingsolid is then partitioned between ether (500 mL) and NaOH solution (1N,200 mL). The organic layer is washed with water (2×100 mL), dried overNa₂ SO₄, and rotary evaporated to yield crudeN-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide(1.75 g). This yellowish oil is purified using silica gel columnchromatography eluting first with ethyl acetate to remove nonpolarimpurities, then with methanol/methylene chloride (50 %) to bring offthe amine (1.1 g; 59%). ¹ H NMR (CDCl₃): 0.90 (3H, t), 1.23 (6H, s),1.30 (22H, s), 1.87 (2H, s), 2.10 (6H, m), 3.73 (2H, s) 4.38 (2H, d),5.38 (2H, t, alkene), 5.93 (1H, br s), 6.83 ppm (3H, s, aromatic). ¹³ CNMR (CDCl₃): 13.77, 22.35, 25.51, 26.05, 26.88, 8.97, 31.53, 36.24,42.74, 49.77, 55.67, 79.09, 111.86, 113.95, 119.73, 129.32, 129.56,131.71, 147.91, 149.58, 172.76 ppm.

EXAMPLE V Carrageenan Rat Paw Edema Test

Compounds of the present invention are tested for anti-inflammatoryactivity using the Carrageenan Rat Paw Edema Test.

Male Sprague Dawley rats (Charles River Breeding Laboratories Inc.) areweighed and food fasted overnight. The animals are divided into four tosix groups of six animals each according to body weights, average about145 g, so that each group has about the same average weight (within 10g).

The following morning five ml of water is dosed orally via stomach tubeto each animal to facilitate paw swelling. Thirty minutes later theanimals are dosed with the test compound and then placed in individualcages. The compound of the present invention is dissolved in distilleddeionized water with 1 equivalent of 1 N acetic acid and delivered viastomach tube in 1 ml volume.

One hour after dosing the test compound, the animals are placed in aplastic restrainer and 50 ul of a 1% (w/w) carrageenan solution in 0.9%saline is injected into the ventral surface of the left rear paw. Pawvolumes (0 time) are determined on both hind paws with a mercurydisplacement device equipped with a transducer and digitizer followingthe carrageenan injection. Four hours after the carrageenan injection,the paw volumes are again determined.

The results are expressed as percent inhibition of the mean paw volumeof the test group relative to the control group according to theformula:

(C-T a..n)/C×100=Percent Inhibition

where C is the average difference in paw volume before and aftercarrageenan-induced swelling, and

Ta..n is the difference in paw swelling in the treated animals (a..n).Statistical differences are determined by one way analysis of variance.

The compoundN-((4-(2-aminoethoxy)-3-methoxyphenyl)methyl)-9Z-octadecenamide of thepresent invention has the following anti-inflammatory activity:

    ______________________________________                                        Dose (mg/kg)   % Inhibition                                                   ______________________________________                                         25            53.5                                                            50            73.7                                                           100            64.9                                                           200            61.4                                                           ______________________________________                                    

EXAMPLE VI Rodent Hot Plate Test

The degree of thermal analgesia obtained is determined using the "rodenthot plate test" (RHP). The RHP system is designed to detect and evaluateagents which elevate the threshold for the perception of pain.Classically, this method has been utilized primarily to evaluate opioid(narcotic) analgesic agents, such as morphine. Unless administered intoxic quantities, antipyretic analgesics, such as aspirin oracetaminophen, exhibit little or no activity in the RHP system.

Male Sprague-Dawley rats (Charles River Breeding Laboratories Inc.)weighing between 100 and 125 grams upon arrival are used to evaluate thecompounds of the present invention. Animals are double housed instainless steel cages, and are fed Purina Rat Chow and tap water adlibitum. The animals are food fasted the afternoon proceeding the day ofthe study, and food is returned 5 hours post-treatment. Animals notbeing dosed by oral gavage are not fasted.

The apparatus for evaluating analgesic activity consists of an insulatedcopper hot plate whose surface is maintained at 55°±0.5° C. by acirculating water bath. A bottomless glass container (12" (30 cm) tallby 8" (20 cm) diameter) is used to restrict the animal to a defined areaof the hot plate. After dosing, the animal is placed through the topopening of the container, and a stop watch is started when the animalmakes contact with the plate. The stop-watch is stopped upon either ofthe following visually observed end points: (1) licking or biting ofeither hind paw, or (2) jumping. If the jump is not successful but bothhind paws leave the surface of the plate in an effort to jump, this isconsidered jumping. The stop-watch is stopped at the end point and theanimal is immediately removed from the hot plate. The time (latency)between the initial contact of the animal on the hot plate and theendpoint is recorded. A 60 second cut off is used during the assay sothat if the end point is not exhibited within 60 seconds, the animal isremoved from the hot plate and given a score of greater than 60 seconds.

Prior to dosing, animals are tested on the hot plate. This is denoted aspretest or base line latency. Usually, the animals are dosed by oralgavage, using a 1 cubic cm glass syringe connected to a size 8 frenchcatheter. The dose volume is 5 ml/kg. On occasion, the animals are dosedby either subcutaneous administration or intravenous injection. Usingthe subcutaneous administration, a 1 ml tuberculin syringe is connectedto a 25 gauge 5/8 inch needle, and injected under the skin in the neckor back region. For intravenous dosing, a 1 ml tuberculin syringe isconnected to a 25 gauge 3/4 inch winged infusion set, and injected intothe tail vein. The dose volume for subcutaneous and intravenous routesis 1 ml/kg. The latency times are typically recorded at 1.5, 3, 5, and24 hours post-treatment. Much shorter times are recorded for anintravenous administration.

The mean latency times for orally dosed compounds of the presentinvention are provided in Tables I, II, and III. The mean latency timesfor orally dosed codeine phosphate are provided in Table IV. Theselatency times indicate that the compounds of the present invention arepotent and efficacious analgesic agents, withN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide beingat least as potent and efficacious as the known opiate codeine.

                  TABLE I                                                         ______________________________________                                        N-((4-(2-aminoethoxy)-3-methoxyphenyl)-                                       methyl)-9Z-octadecenamide                                                              Mean Latency Times -                                                 Dose.sup.1                                                                             Pretest and Hours Post Dose (sec.)                                   (mg/kg)  Pretest   1.5 hr  3 hr   5 hr 24 hr                                  ______________________________________                                         0       7.3       10.4     9.5    8.8  8.4                                    75      8.9       21.8    18.9   18.7 11.2                                   150      9.0       30.6    18.9   15.0 11.5                                   300      7.8       30.7    22.6   21.0 16.5                                   ______________________________________                                         .sup.1 Administered orally; 8 animals per dose group                     

                  TABLE II                                                        ______________________________________                                        N-(9Z-octadecenyl)-4-(2-aminoethoxy)-                                         3-methoxyphenylacetamide                                                               Mean Latency Times -                                                 Dose.sup.1                                                                             Pretest and Hours Post Dose (sec.)                                   (mg/kg)  Pretest   1.5 hr  3 hr   5 hr 24 hr                                  ______________________________________                                         0       8.6       10.2     9.7    8.9 7.7                                    10       7.9        6.7    15.3   13.5 9.1                                    25       7.7       10.5    11.2   10.8 8.0                                    50       7.6       24.5    12.2   10.6 15.9                                   100      7.8       16.4    13.4   11.9 21.5                                   ______________________________________                                         .sup.1 Administered orally; 8 animals per dose group.                    

                  TABLE III                                                       ______________________________________                                        N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanamide                                 Mean Latency Times -                                              Dose.sup.1  Pretest and Hours Post Dose (sec.)                                (mg/kg)     Pretest 3 hr       5 hr 24 hr                                     ______________________________________                                         0          6.1     6.4         6.5  6.8                                       50         6.3     7.5         7.2  8.1                                      100         5.9     9.9        10.2 12.3                                      200         6.8     10.8       16.4 22.0                                      300         6.1     14.1       14.6 20.3                                      ______________________________________                                         .sup.1 Administered orally; 8 animals per dose group.                    

                  TABLE IV                                                        ______________________________________                                        Codeine Phosphate                                                                         Mean Latency Times -                                              Dose.sup.1  Pretest and Hours Post Dose (sec.)                                (mg/kg)     Pretest 1 hr       2 hr 4 hr                                      ______________________________________                                         0          7.3     6.9        6.6  6.2                                        50         7.0     8.7        6.4  6.5                                       100         7.4     8.5        8.9  6.0                                       200         6.9     16.9       21.0 11.7                                      400         6.7     26.5       28.4 24.6                                      ______________________________________                                         .sup.1 Administered orally; 8 animals per dose group.                    

EXAMPLE VII Mouse Abdominal Constriction Assay

Compounds of the present invention are tested for analgesic activityusing the mouse abdominal constriction assay. This assay is described inHendershot and Forsaith, J. Pharmacol. Exp Theraoeut., 125, pp. 237-240(1959); and in Methods in Narcotics Research, Ehrenpreis and Neidle,Eds. (Marcel Dekker, Inc., New York; 1975), pp. 64-65; the disclosuresof both these references being incorporated in their entirety herein byreference.

Male CF-1 mice (Charles River Breeding Laboratories, Inc.), weighingapproximately 20 grams and food fasted overnight, are used in theseassays. Test compounds are prepared for oral (p.o.) or subcutaneous(s.c.) administration, with compounds of the present invention beingprepared in acidified (1 N acetic acid) distilled deionized water sothat the appropriate dose is given in 0.2 mls to a 20 gram mouse.

One and one half hours after administration of the test compoundN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide (p.o.or s.c.), an intraperitoneal (i.p.) injection of 0.02% phenylquinone(2.5 mg/kg) is given at a concentration of 0.25 ml/20 grams body weight.Ten minutes after the i.p. injection of phenylquinone, the number offull body writhes are counted for the succeeding ten minutes. Percentanalgesia in this assay is calculated as follows: ##EQU1##

The oral dose response and subcutaneous dose response forN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide of thepresent invention are provided in Table V and Table VI respectively. Theoral dose response and subcutaneous dose response forN-vanillyloleamide, which is disclosed in U.S. Pat. No. 4,493,848 toLaHann and Buckwalter, issued Jan. 15, 1985, are provided in Table VIIand Table VIII respectively. The N-vanillyloleamide is tested foranalgesic activity at 3 hours postdose rather than at 1.5 hourspost-dose since this is the time at which this compound demonstrates itspeak analgesic effect.

The N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamidecompound of the present invention is structurally the same as theN-vanillyloleamide except for the 2-aminoethoxy substitution on thephenyl ring. However, compared with the N-vanillyloleamide dosed orally,the compound of the present invention dosed orally demonstratessubstantially greater analgesic potency at a substantially lower dose.

                  TABLE V                                                         ______________________________________                                        Oral Dose Response for                                                        N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-                               9Z-octadecenamide                                                             Dose (mg/kg)   % Analgesia                                                    ______________________________________                                        10             55.8                                                           25             71.7                                                           75             88.3                                                           150            95.5                                                           300            93.2                                                           ______________________________________                                    

                  TABLE VI                                                        ______________________________________                                        Subcutaneous Dose Response for                                                N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-                               9Z-octadecenamide                                                             Dose (mg/kg)   % Analgesia                                                    ______________________________________                                        1              22.3                                                           2              -13.7                                                          4              34.3                                                           8              57.8                                                           10             91.4                                                           100            99.0                                                           ______________________________________                                    

                  TABLE VII                                                       ______________________________________                                        Oral Dose Response for N-Vanillyloleamide.sup.1                               Dose (mg/kg) % Analgesia (3 hrs post-dose).sup.2                              ______________________________________                                        100          36                                                               200          60                                                               400          79                                                               ______________________________________                                         .sup.1 Disclosed in U.S. Pat. No. 4,493,848, to LaHann and Buckwalter,        issued January 15, 1985.                                                      .sup.2 At time of peak analgesic effect.                                 

                  TABLE VIII                                                      ______________________________________                                        Subcutaneous Dose Response for N-Vanillyloleamide.sup.1                       Dose (mg/kg) % Analgesia (3 hrs post-dose).sup.2                              ______________________________________                                        0.75         35.4                                                             1.5          62.8                                                             2.25         76.1                                                             ______________________________________                                         .sup.1 Disclosed in U.S. Pat. No. 4,493,848, to LaHann and Buckwalter,        issued January 15, 1985                                                       .sup.2 At time of peak analgesic effect.                                 

EXAMPLE VIII

A composition for oral administration is prepared by combining thefollowing ingredients:

    ______________________________________                                        N-((4-(2-aminoethoxy)-3-methoxyphenyl)-                                                                 1.10 kg                                             methyl)-9Z-octadecenamide                                                     Sesame oil                6.50 liters                                         ______________________________________                                    

The octadecenamide is dissolved in the sesame oil with the aid ofsonication and is packaged in soft gelation capsules using methods knownin the art. Two of the resulting capsules, each containing 225 mg of thecomposition, are administered to a 60 kg human in need of treatment,producing analgesia and reducing inflammation.

A substantially similar reduction of inflammation and an increasedanalgesic effect is obtained when theN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide isreplaced with N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2(S)-amino-3-methylbutoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-octanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-((4-(2-amino-3-hydroxypropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-amino-2-carboxyethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;and the pharmaceutically-acceptable salts and amides thereof.

Capsules for oral administration are also prepared by combining thefollowing ingredients:

    ______________________________________                                        N-((4-(2-aminoethoxy)-3-methoxyphenyl)-                                                               100 mg                                                methyl)-9Z-octadecenamide                                                     Lactose                 50 mg                                                 Microcrystalline cellulose                                                                            50 mg                                                 ______________________________________                                    

EXAMPLE IX

A composition for oral administration is prepared by combining thefollowing ingredients:

    ______________________________________                                        N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxy-                                                           250    g                                          phenylacetamide                                                               Propylene glycol            1800   ml                                         Ethyl alcohol               175    ml                                         Distilled water             75     ml                                         Artificial Cherry flavor    10     ml                                         FD&C Red #40                0.2    g                                          ______________________________________                                    

The above ingredients are combined to produce a syrup and are packagedunder sterile conditions in 6 oz. bottles. One teaspoon of thisformulation is administered to a 70 kg adult human, reducinginflammation and producing analgesia.

A substantially similar reduction of inflammation and analgesic effectis obtained when theN-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide isreplaced withN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2aminoethoxy)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2(S)-amino-3-methylbutoxy)-3-methoxyphenyl)methyl)-9Z-octadecenamide;N-octanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-((4-(2-amino-3-hydroxypropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-amino-2-carboxyethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;and the pharmaceutically-acceptable salts and amides thereof.

EXAMPLE X

A composition for topical administration is prepared by combining thefollowing ingredients:

    ______________________________________                                        N-((4-(2-methyl-2-aminopropoxy)-3-                                                                      4      g                                            methoxyphenyl)-methyl)-9Z-octadecenamide                                      Propylene glycol          100    ml                                           Ethyl alcohol             100    ml                                           ______________________________________                                    

The octadecenamide is dissolved in a solution containing the otheringredients. Application of 0.4 ml of the resulting liquid to a 80 cm²portion of the forearm of a 60 kg human produces local analgesia whichlasts approximately two days. Little or no skin irritation is observed.

A substantially similar local analgesic effect is obtained when theN-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamideis replaced withN-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(2-(S)-amino-3-methylbutoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-octanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-((4-(2-amino-3-hydroxypropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-amino-2-carboxyethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;and the pharmaceutically-acceptable salts and amides thereof.

EXAMPLE XI

Tablets are prepared by conventional methods, such as mixing and directcompaction, formulated as follows:

    ______________________________________                                        Ingredient         mg per tablet                                              ______________________________________                                        N-((4-(2-aminoethoxy)-3-                                                                         100                                                        methoxyphenyl)-methyl)-                                                       nonanamide                                                                    Microcrystalline cellulose                                                                       100                                                        Sodium Starch glycolate                                                                           30                                                        Magnesium stearates                                                                               5                                                         ______________________________________                                    

One tablet is administered orally to a patient in need of analgesia twotimes daily to provide general analgesia.

Similar results are achieved with tablets formulated as above butreplacing the N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanamidewith N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2(S)-amino-3-methylbutoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-octanyl-4-(2-aminoethoxy)-3-methoxyphenylacetamide;N-((4-(2-amino-3-hydroxypropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-amino-2-carboxyethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;and the pharmaceutically-acceptable salts and amides thereof.

EXAMPLE XII

Injectable compositions are prepared as follows:

    ______________________________________                                        Component                 Weight %                                            ______________________________________                                        Composition 1:                                                                N-((4-(2-aminoethoxy)-3-methoxyphenyl)-                                                                 0.05%                                               methyl)-9Z-octadecenamide                                                     Aqueous Acetic Acid (1.30%)                                                                             95.45%                                              Dextrose                  4.50%                                               Composition 2:                                                                N-((4-(2-aminoethoxy)-3-methoxyphenyl)-                                                                 0.05%                                               methyl)-9Z-octadecenamide                                                     Aqueous Sodium Acetate (1.18%)                                                                          85.95%                                              Aqueous Acetic Acid (2.0%)                                                                              10.00%                                              Benzyl Alcohol            4.00%                                               Composition 3:                                                                N-((4-(2-aminoethoxy)-3-methoxyphenyl)-                                                                 0.05%                                               methyl)-nonanamide                                                            Propylene Glycol          99.95%                                              Composition 4:                                                                N-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-                                                                 0.05%                                               methoxyphenylacetamide                                                        Polyethylene Glycol: Propylene Glycol (1:3)                                                             99.95%                                              ______________________________________                                    

The injection of 0.05 ml of Composition 2 prior to oral surgery for a3rd molar extraction provides local anesthesia during the surgery andlong-lasting local analgesia following the surgery. Similar localanalgesia benefits are obtained by locally infiltrating the surgicalsite with Compositions 1, 3 or 4 immediately following a surgery toprovide long-lasting analgesia for surgical site pain.

EXAMPLE XIII N-(4-(2-nitrophenoxy)-3-methoxyphenylmethyl)nonanamide

In a 50 mL flask is placed a 24% potassium hydride dispersion (4.11grams). The flask is stoppered and flushed with argon. Drytetrahydrofuran (5 mL) is syringed into the flask. The mixture isstirred briefly and then the potassium hydride is allowed to settle. Thetetrahydrofuran is removed with a syringe.4-Hydroxy-3-methoxy-phenylmethylnonanamide (3.00 grams) is dissolved indry N,N-dimethylformamide (15 mL) and slowly syringed into the flask.Hexamethylphosphoramide (4.0 mL) is syringed into the flask. The mixtureis stirred under argon for one hour. 1-Chloro-2-nitrobenzene (3.56grams) dissolved in dry N,N-dimethylformamide (5 mL) is syringed intothe flask. The mixture is heated at 52° C. for 18 hours. Rotaryevaporation of the solvents affords a residue which is mixed with 10%aqueous citric acid (50 mL), ethyl acetate (500 mL) and benzene (100mL). The organic layer is washed with water (13×200 mL), dried oversodium sulfate, and rotary evaporated to a volume of about 15 mL. Thissolution is chromatographed on silica gel (Kieselgel 60 silica gel,230-400 mesh) eluting with a mixture of ethyl acetate/hexanes (20/80)followed with ethyl acetate/hexanes (75/25). Rotary evaporation of thecompound-containing fractions yields 3.997 grams crude product which iscrystallized from hot ethyl acetate and hexanes to giveN-(4-(2-nitrophenoxy)-3-methoxyphenylmethyl)nonanamide (2.86 g, 72%, mp93°-93.5° C.).

N-(4-(2-aminoohenoxy)-3-methoxvohenvlmethyl)nonanamide

N-(4-(2-nitrophenoxy)-3-methoxyphenylmethyl)nonanamide (1.23 g) isdissolved in methanol (50 mL). To this is added 10% palladium oncharcoal (100.1 mg). The mixture is placed on a Paar shaker for 60minutes at room temperature and 42 psi hydrogen. The mixture is filteredthrough celite, evaporated to dryness on a rotary evaporator, then driedovernight at room temperature and reduced pressure (0.5 mm Hg) to yieldN-(4-(2-aminophenoxy)-3-methoxyphenylmethyl)nonanamide (1.11 g, 97%).

What is claimed is:
 1. Beta-aminoethyl-substituted phenyl compoundswhich are effective as anti-inflammatory or analgesic agents, and thepharmaceutically-acceptable salts and amides thereof, having the generalstructure: ##STR45## wherein: (a) the --W--X-- moiety is selected fromthe group consisting of --C(O)NH--, --C(S)NH--, --S(O)₂ NH--,--NHC(O)O--, --NHC(S)O--, --NHC(O)NH-- and --NHC(S)NH-- wherein eitheravailable bond of the --W--X-- moiety is bonded to the --R moiety andthe remaining bond is attached to the benzyl carbon atom;(b) --Y-- is amoiety selected from the group consisting of --O--, --S-- and --NR⁴ --,where --R⁴ is selected from hydrogen and C₁ -C₄ alkanyl; (c) --Z isselected from the group consisting of hydrogen, hydroxy, and methoxy;(d) --R is an alkyl group having from about 1 to about 24 carbon atoms;(e) --R¹ is selected from the group consisting of hydrogen, hydroxy,alkyl esters of hydroxy having from about 1 to about 5 carbon atoms,alkyl having from about 1 to about 5 carbon atoms, and alkoxy havingfrom about 1 to about 5 carbon atoms; and (f) each --R² is independentlyselected from hydrogen, halogen, unsubstituted or substituted alkylhaving from about 1 to about 6 carbon atoms, substituted orunsubstituted aryl, and carboxylate, or two --R² moieties are covalentlybonded to form a substituted or unsubstituted alkyl or aryl ring havingfrom about 3 to about 8 carbon atoms in the ring; wherein any alkyl ringsubstituent is selected from the group consisting of halogen, hydroxy,amino, aryl, carboxylate, and --OR³ wherein --R³ is unsubstituted alkylhaving from about 1 to about 3 carbon atoms; and wherein any arylsubstituent is selected from the group consisting of halogen, hydroxy,C₁ -C₁₆ alkoxy, amino, nitro, cyano, phenyl, benzyl, benzyloxy,trifluoromethyl, formylamino, carboxylate and C₁ -C₆ alkyl. 2.Beta-aminoethyl-substituted phenyl compounds, and thepharmaceutically-acceptable salts and amides thereof, according to claim1, wherein --Y-- is --O--, and --R¹ is selected from the groupconsisting of hydrogen, hydroxy, and methyl. 3.Beta-aminoethyl-substituted phenyl compounds, and thepharmaceuticlly-acceptable salts and amides thereof, according to claim2, wherein --R¹ is hydrogen; both --R² on the alpha carbon atom arehydrogen; both --R² on the beta carbon atom are selected from hydrogenand alkyl having from 1 to about 5 carbon atoms or the --R² arecovalently bonded to form an alkyl ring having from about 3 to about 6carbon atoms, the alkyl or alkyl ring being unsubstituted or substitutedwith phenyl; and --Z is methoxy.
 4. Beta-aminoethyl-substituted phenylcompounds which are effective as anti-inflammatory or analgesic agents,and the pharmaceutically-acceptable salts and amides thereof, having thegeneral structure: ##STR46## wherein: (a) ═Q is selected from the groupconsisting of oxygen or sulfur;(b) --Y-- is a moiety selected from thegroup consisting of --O--, --S-- and --NR⁴ --, where --R⁴ is selectedfrom hydrogen and C₁ -C₄ alkanyl; (c) --Z is selected from the groupconsisting of hydrogen, hydroxy, and methoxy; (d) --R is an alkyl grouphaving from about 1 to about 24 carbon atoms; (e) --R¹ is selected fromthe group consisting of hydrogen, hydroxy, alkyl esters of hydroxyhaving from about 1 to about 5 carbon atoms, alkyl having from about 1to about 5 carbon atoms, and alkoxy having from about 1 to about 5carbon atoms; and (f) each --R² is independently selected from hydrogen,halogen, unsubstituted or substituted alkyl having from about 1 to about6 carbon atoms, substituted or unsubstituted aryl, and carboxylate, ortwo --R² moieties are covalently bonded to form a substituted orunsubstituted alkyl or aryl ring having from about 3 to about 8 carbonatoms in the ring; wherein any alkyl ring substituent is selected fromthe group consisting of halogen, hydroxy, amino, aryl, carboxylate, and--OR³ wherein --R³ is unsubstituted alkyl having from about 1 to about 3carbon atoms; and wherein any aryl substituent is selected from thegroup consisting of halogen, hydroxy, C₁ -C₁₆ alkoxy, amino, nitro,cyano, phenyl, benzyl, benzyloxy, trifluoromethyl, formylamino,carboxylate and C₁ -C₆ alkyl.
 5. Beta-aminoethyl-substituted phenylcompounds, and the pharmaceutically-acceptable salts and amides thereof,according to claim 4, wherein --Y-- is --O--, and --R¹ is selected fromthe group consisting of hydrogen, hydroxy and methyl. 6.Beta-aminoethyl-substituted phenyl compounds, and thepharmaceutically-acceptable salts and amides thereof, according to claim5, wherein ═Q is oxygen.
 7. Beta-aminoethyl-substituted phenylcompounds, and the pharmaceutically-acceptable salts and amides thereof,according to claim 6, wherein --R¹ is hydrogen; both --R² on the alphacarbon atom are hydrogen; both --R² on the beta carbon atom are selectedfrom hydrogen and alkyl having from 1 to about 5 carbon atoms or the--R² are covalently bonded to form an alkyl ring having from about 3 toabout 6 carbon atoms, the alkyl or alkyl ring being unsubstituted orsubstituted with phenyl; and --R is selected from the group consistingof alkanyl groups having from about 6 to about 14 carbon atoms, alkenylgroups having from about 14 to about 22 carbon atoms, and alkynyl groupshaving from about 14 to about 22 carbon atoms. 8.Beta-aminoethyl-substituted phenyl compounds, and thepharmaceutically-acceptable salts and amides thereof, according to claim7, wherein --Z is methoxy; and --R is selected from the group consistingof n-hexanyl, n-heptanyl, n-octanyl, n-nonanyl, n-decanyl, n-undecanyl,n-dodecanyl, n-tridecanyl, n-tetradecanyl, tetradecenyl, pentadecenyl,hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl,docosenyl, octadecadienyl, nonadecadienyl, eicosadienyl,octadecatrienyl, eicosatrienyl, eicosatetraenyl, octadecynyl,nonadecynyl, eicosynyl, and docosynyl.
 9. Beta-aminoethyl-substitutedphenyl compounds, and the pharmaceutically-acceptable salts and amidesthereof, according to claim 8, wherein both --R² on the beta carbon atomare selected from the group consisting of hydrogen, methyl, ethyl, andboth --R² being covalently bonded to form a C₃ -C₅ saturated alkyl ring;and --R is selected from the group consisting of n-octanyl; n-nonanyl;n-decanyl; 9E- or 9Z-tetradecenyl; 9E- or 9Z-hexadecenyl; 9E- or9Z-octadecenyl; 6E- or 6Z-octadecenyl; 11E- or 11Z-octadecenyl; 10E- or10Z-nonadecenyl; 13E- or 13Z- docosenyl; 9-methylene-1-octadecanyl;9Z,12Z-octadecadienyl; 9E, 12E-octadecadienyl; 9Z, 12E-octadecadienyl;9Z, 11E-octadecadienyl; 10E, 13E-nonadecadienyl; 11E,14E-eicosadienyl;9Z, 12Z, 15Z-octadecatrienyl; 6Z, 9Z, 12Z-octadecatrienyl; 11Z, 14Z,17Z-eicosatrienyl; 5Z, 8Z, 11Z, 14Z-eicosatetraenyl; and 9-octadecynyl.10. Beta-aminoethyl-substituted phenyl compounds, and thepharmaceutically-acceptable salts and amides thereof, according to claim9, selected from the group consisting ofN-(9Z-octadecenyl)-4-(2-aminoethoxy)-3-methoxyphenylacetamide,N-octanyl-4(2-aminoethoxy)-3-methoxyphenylacetamide,N-(9Z-octadecenyl)-4-(2-amino-2-methylpropoxy)-3-methoxyphenylacetamide,and N-octanyl-4-(2-amino-2-methylpropoxy)-3-methoxyphenylacetamide. 11.Beta-aminoethyl-substituted phenyl compounds, and thepharmaceutically-acceptable salts and amides thereof, according to claim7, where both --R² on the alpha carbon atoms are hydrogen and both --R²on the beta carbon atom are methyl.
 12. Beta-aminoethyl-substitutedphenyl compounds, and the pharmaceutically-acceptable salts and amidesthereof, according to claim 7, where all --R² are hydrogen. 13.Beta-aminoethyl-substituted phenyl compounds which are effective asanti-inflammatory or analgesic agents, and thepharmaceutically-acceptable salts and amides thereof, having the generalstructure: ##STR47## wherein: (a) ═Q is selected from the groupconsisting of oxygen or sulfur;(b) --Y-- is a moiety selected from thegroup consisting of --O--, --S-- and --NR⁴ --, where --R⁴ is selectedfrom hydrogen and C₁ -C₄ alkanyl; (c) --Z is selected from the groupconsisting of hydrogen, hydroxy, and methoxy; (d) --R is an alkyl grouphaving from about 1 to about 24 carbon atoms; (e) --R¹ is selected fromthe group consisting of hydrogen, hydroxy, alkyl esters of hydroxyhaving from about 1 to about 5 carbon atoms, alkyl having from about 1to about 5 carbon atoms, and alkoxy having from about 1 to about 5carbon atoms; and (f) each --R² is independently selected from hydrogen,halogen, unsubstituted or substituted alkyl having from about 1 to about6 carbon atoms, substituted or unsubstituted aryl, and carboxylate, ortwo --R² moieties are covalently bonded to form a substituted orunsubstituted alkyl or aryl ring having from about 3 to about 8 carbonatoms in the ring; wherein any alkyl ring substituent is selected fromthe group consisting of halogen, hydroxy, amino, aryl, carboxylate, and--OR³ wherein --R³ is unsubstituted alkyl having from about 1 to about 3carbon atoms; and wherein any aryl substituent is selected from thegroup consisting of halogen, hydroxy, C₁ -C₁₆ alkoxy, amino, nitro,cyano, phenyl, benzyl, benzyloxy, trifluoromethyl, formylamino,carboxylate and C₁ -C₆ alkyl.
 14. Beta-aminoethyl-substituted phenylcompounds, and the pharmaceutically-acceptable salts and amides thereof,according to claim 13, wherein --Y-- is --O--, and --R¹ is selected fromthe group consisting of hydrogen, hydroxy and methyl. 15.Beta-aminoethyl-substituted phenyl compounds, and thepharmaceutically-acceptable salts and amides thereof, according to claim14, wherein ═Q is oxygen.
 16. Beta-aminoethyl-substituted phenylcompounds, and the pharmaceutically-acceptable salts and amides thereof,according to claim 15, wherein --R¹ is hydrogen; both --R² on the alphacarbon atom are hydrogen; both --R² on the beta carbon atom are selectedfrom hydrogen and alkyl having from 1 to about 5 carbon atoms or the--R² are covalently bonded to form an alkyl ring having from about 3 toabout 6 carbon atoms, the alkyl or alkyl ring being unsubstituted orsubstituted with phenyl; and --R is selected from the group consistingof alkanyl groups having from about 6 to about 14 carbon atoms, alkenylgroups having from about 14 to about 22 carbon atoms, and alkynyl groupshaving from about 14 to about 22 carbon atoms. 17.Beta-aminoethyl-substituted phenyl compounds, and thepharmaceutically-acceptable salts and amides thereof, according to claim16, wherein --Z is methoxy; and --R is selected from the groupconsisting of n-hexanyl, n-heptanyl, n-octanyl, n-nonanyl, n-decanyl,n-undecanyl, n-dodecanyl, n-tridecanyl, tridecenyl, tetradecenyl,pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl,eicosenyl, docosenyl, heptadecadienyl, octadecadienyl, nonadecadienyl,eicosadienyl, heptadecatrienyl, octadecatrienyl, nonadecatrienyl,eicosatrienyl, nonadecatetraenyl, heptadecynyl, octadecynyl,nonadecynyl, and eicosynyl.
 18. Beta-aminoethyl-substituted phenylcompounds, and the pharmaceutically-acceptable salts and amides thereof,according to claim 17, selected from the group consisting ofN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanamide;N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2(S)-amino-3-methylbutoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;N-((4-(2-amino-3-hydroxypropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide;andN-((4-(2-amino-2-carboxyethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide19. Beta-aminoethyl-substituted phenyl compounds, and thepharmaceutically-acceptable salts and amides thereof, according to claim17, wherein both --R² on the beta carbon atom are selected from thegroup consisting of hydrogen, methyl, ethyl, and both --R² beingcovalently bonded to form a C₃ -C₅ saturated alkyl ring; and --R isselected from the group consisting of n-heptanyl; n-octanyl; n-nonanyl;8E- or 8Z-tridecenyl; BE- or 8Z-pentadecenyl; 8E- or 8Z-heptadecenyl;5E- or 5Z-heptadecenyl; 10E- or 10Z-heptadecenyl; 9E- or 9Z-octadecenyl;12E- or 12Z-nonadecenyl; 8-methylene-1-heptadecanyl; 8Z,11Z-heptadecadienyl; 8E, 11E-heptadecadienyl; 8Z, 11E-heptadecadienyl;8Z, 10E-heptadecadienyl; 9E, 12E-octadecadienyl; 10E,13E-nonadecadienyl;8Z, 11Z, 14Z-heptadecatrienyl; 5Z, 8Z, 11Z-heptadecatrienyl; 10Z, 13Z,16Z-nonadecatrienyl; 4Z, 7Z, 10Z, 13Z-nonadecatetraenyl; and8-heptadecynyl.
 20. Beta-aminoethyl-substituted phenyl compounds, andthe pharmaceutically-acceptable salts and amides thereof, according toclaim 19, selected from the group consisting ofN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide,N-((4(2-aminoethoxy)-3-methoxyphenyl)-methyl)-nonanamide,N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide,and N-((4-(2-methyl-2-aminopropoxy)-3-methoxyphenyl)-methyl)nonanamide.21. Beta-aminoethyl-substituted phenyl compounds, and thepharmaceutically-acceptable salts and amides thereof, according to claim16, wherein both --R² on the alpha carbon atoms are hydrogen and both--R² on the beta carbon atom are methyl.
 22. Beta-aminoethyl-substitutedphenyl compounds, and the pharmaceutically-acceptable salts and amidesthereof, according to claim 16, where all --R² are hydrogen. 23.Beta-aminoethyl-substituted phenyl compounds, and thepharmaceutically-acceptable salts and amides thereof, according to claim19, wherein the compound isN-((4-(2-aminoethoxy)-3-methoxyphenyl)-methyl)-9Z-octadecenamide. 24.Pharmaceutical compositions comprising:(a) a safe and effective amountof a compound according to any of claim 1, 3, 4, 7, 9, 13, 16, or 19;and (b) a pharmaceutically-acceptable carrier.